Linear polysaccharide based film products

ABSTRACT

Film products, especially suitable for oral delivery, which can be formed during manufacture in the form of large and/or heavy film strips or sheets and subsequently cut into uniform dosage units, each dosage unit being uniform in content and having distributed therein a linear polysaccharide, such as pullulan, a plasticizer, and an active component.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit to U.S. Provisional Application No.62/089,676 filed Dec. 9, 2014.

FIELD OF THE INVENTION

The invention relates to pharmaceutical film products, especiallysuitable for oral delivery, which can be formed during manufacture inthe form of large and/or heavy film strips or sheets and subsequentlycut into uniform dosage units, each dosage unit being uniform in activecontent and having distributed therein a linear polysaccharide as thepolymer platform, such as pullulan, a plasticizer, other film formingexcipients, and an active component.

BACKGROUND OF RELATED TECHNOLOGY

Pullulan is a relatively high molecular weight polymer yet has lowviscosity and high solids loading due to its high water solubility. Forexample, a 10% solids solution of pullulan with an average molecularweight of 200,000 Daltons in 30° C. water has a viscosity of 130-180centipoise. Films made with Pullulan tend to dissolve quickly. However,Pullulan also has some negative properties when it is manufactured onhigh speed mixing equipment. Used alone, it is brittle and shocksensitive and if plasticized, it is difficult to incorporate sufficientplasticizer into the formulation to decrease or eliminate shocksensitivity without the film becoming tacky. To get around these adverseproperties, water is often used as a plasticizer with and withoutstarch, xanthan and gellan gum. The films are dried with relatively highamounts of moisture left in the film, as much as 5-10%. However, highmoisture content can increase the water activity of the film strips andthus become a breeding ground for microbial growth. Also, water(moisture content) tends to evaporate from such formulations over timeand the loss of the plasticizer (water) leads to brittleness of thefinished film as the film ages.

Low tackiness, lack of shock sensitivity and lack of brittleness are allimportant physical attributes of a robust “production quality” polymerformulation for oral soluble films. The manufactured oral soluble filmweb undergoes many unit operations during the drying, slitting, storingand packaging production steps. Film webs with improper adhesion orrelease characteristics can result in jamming of the packaging linewhich brings the manufacturing process to a halt. The same jammingoccurs with any film web that is brittle. Shock sensitivity is alsoimportant attribute of the film web, especially during the film slittingprocess, as a shock sensitive film web will experience crazing, andshatter like a broken glass, rather than propagating the failure in thedirection of the knife, which results in a clean and even cut likepaper. This leads to unusable product and a stalled low-yieldmanufacturing process.

Self-supporting linear polysaccharide (e.g., glucan) films, such asthose made from pullulan and elsinan, are known as being useful for thedelivery of edible or ingestible components (e.g., commercial breathfilms), for packaging and wrapping as well as other uses. For example,U.S. Pat. No. 4,562,020 to Haijiya, et al. discloses a continuousprocess for producing such self-supporting glucan films formed fromaqueous glucan solutions whereby the solution is deposited on acorona-treated plastic conveyor belt and air dried to form films.

U.S. Pat. No. 4,927,636 to Haijiya, et al. discloses pullulan filmswhich have decreased solubility in water. These films are made from acombination of pullulan and polyethylene glycol (PEG) which form an“association complex” to produce this effect. Polyethylene glycolswithin the molecular weight range of 400 to 10,000 Daltons are disclosedas useful. The ratio of pullulan to PEG is disclosed as being 1 part byweight (pbw) pullulan to 0.01 to 100 part by weight (pbw) PEG. Thispatent discloses that pullulan in combination with other water-solublepolymers does not form such an association complex useful for decreasingsolubility and reducing adhesive and stickiness properties of aqueouspullulan.

U.S. Pat. No. 5,411,945 to Ozaki, et al. discloses a pullulan bindercomposition made from a combination of pullulan and a mono-saccharide orlower molecular weight oligo-saccharide in a ratio of 85:15 to 65:35pullulan/saccharide. These films are disclosed as being graduallydissolvable.

U.S. Pat. No. 5,518,902 to Ozaki, et al. discloses high pullulan contentproducts made by cultivating micro-organisms capable of producingpullulan at a pH exceeding 2.0 but not higher than 4.0 in a nutrientculture medium containing 10-20 w/v % of a polysaccharide to producepullulan, while controlling the viscosity of the nutrient culture tobelow 30 cps.

U.S. Patent Application Publication No. 2001/0022964 A1 to Leung, et al.discloses edible films made from pullulan and which includeanti-microbial effective amounts of essential oils.

While various active pharmaceutical ingredients may be included in thefilms, the content of pullulan used is very high and the drug loading isvery low, as is typical of pullulan films. In addition, a variety ofpolymers may be used as film formers in addition to pullulan.

It would be desirable to have film products made from pullulan which caninclude high content of active pharmaceutical ingredients, such aspharmaceutical and/or cosmetic agents, and which have relatively lowpullulan content. It would also be desirable to manufacture “productionquality” film products containing pullulan that are robust enough towithstand high speed production and packaging unit operations and thatwill stay flexible over time after the packaging operation. It wouldalso be advantageous to provide water-soluble and/or dispersible, ediblefilms which have a uniformity of active pharmaceutical ingredientcontent, both at production scale and in the packaged unit, whereby theactive content of the final unit dose film product varies by no morethan 10% from the desired level of active pharmaceutical ingredient.

SUMMARY OF THE INVENTION

The present invention seeks to attain low polymer content, highpharmaceutical and/or cosmetic active content orally dissolvable filmswhich have enhanced flexibility, structural integrity, uniformity, andpossess disintegration and/or dissolution times of less than 5 minuteswhen placed into contact with any of several body surfaces, especiallythose including mucosal surfaces, such as those found in the oral (i.e.,sublingual, lingual, buccal, and gingival), anal, vaginal, ocular,nasal, aural, ophthalmological, and peritoneal environments; the surfaceof a wound, either on a skin surface or within the body such as duringsurgery or left in place after surgery to deliver the desired amount ofactive after the surgical procedure is completed; the surface of anorgan (i.e., kidney, lung, liver, heart, etc.), and other similarsurfaces. In certain instances, in the film products of the inventionfour to five times more film weight can be loaded into the same sizefilm (area) and while maintaining a similar Partial ImmersionDissolution (PID) time when compared to traditional polymer filmformulations.

In an embodiment, the films of the invention have a disintegrationand/or dissolution time is less than about 4 minutes, less than about 3minutes, less than about 2 minutes, less than about 1.5 minutes, lessthan 1 minute, less than about 45 seconds, less than about 30 seconds,less than about 20 seconds, less than about 15, seconds, less than about10 seconds, or less then about 5 seconds. In embodiments, thedisintegration and/or dissolution time is in the range of from about 5seconds to about 5 minutes, from about 10 second to about 4 minutes,from about 15 seconds to about 2 minutes, from about 20 seconds to about1.5 minutes, from about 30 second to about 90 seconds, or about 5seconds to about 1 minute.

In one embodiment of the present invention, there is provided a filmproduct including: a. at least one linear polysaccharide; b. atherapeutically effective amount of at least one active component; andc. at least one plasticizer.

In a further embodiment of the present invention, there is provided afilm product including: a. pullulan; b. a therapeutically effectiveamount of sildenafil or a pharmaceutically acceptable salt thereof; andc. at least one plasticizer.

In one embodiment of the present invention, there is provided a filmproduct including: a. pullulan; b. a therapeutically effective amount ofa pregabalin; and c. at least one plasticizer.

In one embodiment of the present invention, there is provided a filmproduct including: a. pullulan; b. a therapeutically effective amount oftadalafil; and c. at least one plasticizer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a comparison of the partial immersion dissolution time forthe comparative film compositions (HPMC/PEO) and inventive film products(Pullulan).

FIG. 2 shows the partial immersion dissolution time data for thecomparative film compositions and inventive film products and includesan extrapolation of the partial immersion dissolution time for greaterweights of film.

FIG. 3 shows the plasma sildenafil levels for individual dogs dosed witha 50 mg Viagra™ tablet.

FIG. 4 shows the plasma sildenafil levels for individual dogs dosed witha film product of the invention containing sildenafil citrate in a 50 mgbase equivalent amount.

FIG. 5 shows the plasma sildenafil levels for individual dogs dosed witha film product of the invention containing sildenafil citrate in a 50 mgbase equivalent amount in a gelatin capsule.

FIG. 6 shows the plasma sildenafil levels for individual dogs dosed witha film product of the invention containing sildenafil resinate in a 50mg base equivalent amount.

FIG. 7 shows the mean plasma sildenafil levels for dogs dosed with a 50mg Viagra™ tablet.

FIG. 8 shows the mean plasma sildenafil levels for dogs dosed with afilm product of the invention containing sildenafil citrate in a 50 mgbase equivalent amount.

FIG. 9 shows the mean plasma sildenafil levels for dogs dosed with afilm product of the invention containing sildenafil citrate in a 50 mgbase equivalent amount in a gelatin capsule.

FIG. 10 shows the mean plasma sildenafil levels for dogs dosed with afilm product of the invention containing sildenafil resinate in a 50 mgbase equivalent amount.

FIG. 11 shows a comparison of the mean plasma sildenafil levels for dogsdosed with a 50 mg Viagra™ tablet, dogs dosed with a film product of theinvention containing sildenafil citrate in a 50 mg base equivalentamount, dogs dosed with a film product of the invention containingsildenafil citrate in a 50 mg base equivalent amount in a gelatincapsule, and dogs dosed with a film product of the invention containingsildenafil resinate in a 50 mg base equivalent amount from dosing to 10hours post-dosing.

FIG. 12 shows a comparison of the mean plasma sildenafil levels for dogsdosed with a 50 mg Viagra™ tablet, dogs dosed with a film product of theinvention containing sildenafil citrate in a 50 mg base equivalentamount, and dogs dosed with a film product of the invention containingsildenafil citrate in a 50 mg base equivalent amount in a gelatincapsule from dosing to 2.5 hours post-dosing.

FIG. 13 shows the dissolution profile for sildenafil from sildenafilcitrate films initially and stored for up to 4 weeks at 25° C. and 60%relative humidity or 40° C. and 75% relative humidity.

DETAILED DESCRIPTION OF THE INVENTION

The term “linear polysaccharide” means polymeric compounds includinglong chains of monosaccharaides bound to one another though glycosidicbonds and having a substantially linear structure. As used herein“polysaccharide” may include any molecule including more than 2monosaccharides bound together. In aspects of the invention, the linearpolysaccharide is a polysaccharide with an alpha 1,4 or and alpha 1,6glycosidic linkage.

Preferably the linear polysaccharides of the invention have low glasstransition temperatures (less than room temperature). For example, glasstransition temperatures for pullulan, dextrose, and amylose are −73° C.,−94° C., and −59° C. respectively. In particular, preferredpolysaccharides of the invention have β(1-4 glycosidic bonds) and α(1-4glycosidic bonds), which offer exceptional rotational freedom. β(1-4glycosidic bonds) are favored in linear or stretched chain conformationsand are favorable because they resist the helical conformationassociated with α(1-4 glycosidic bonds) and the semicrystallinestructure that accompanies it. In either case, the low glass transitiontemperature affords sufficient free volume for highly loaded films,while affording the mechanical integrity for a flexible, manufacturablefilm.

Linear polysaccharides for use in the present invention include glucans.As used herein, “Glucan” means a polysaccharide of D-glucosemonosaccharides bound to one another through glycosidic bonds.

Glucans useful in the present invention include pullulan and elsinanThese materials substantially contain repeating maltotriose units andare produced by culturing a strain of species Aureobasidium pullulans orgenus Elsino on a nutrient medium containing sugars under aeration andagitation conditions. The cellular debris is removed and the resultantsupernatant is purified and filtered to yield the resultant glucan. Themolecular weight of the glucan may vary widely, but generally arecommercially available in grades that are designated as having molecularweights of about 8,000 to greater than 2,000,000 Daltons. Preferably,the glucan of the present invention is designated as having a molecularweight between about 25,000 and about 500,000 Daltons, more preferably,between about 50,000 to about 200,000 Daltons. It is well understoodthat these grades are blends of molecular weights and not absolutevalues.

In aspects of the invention, the linear polysaccharide is maltose 1,4;raffinose 1-6; meibiose 1,6; laltotriose 1,4; maltotriose 1,4;maltotetralose 1,4; maltopentalose 1,4; linear dextrins 1,4; lineardextrins 1,6; or combinations thereof.

The linear polysaccharide may be present in amounts up to about 75% byweight of the total composition and desirably in amounts of up to about40% by weight of the total composition. In aspects of the invention thelinear polysaccharide may be present in amounts of about 10% to about35% by weight of the total composition. In other aspects of theinvention the linear polysaccharide may be present in amounts of about15% to about 25% by weight of the total composition. In an aspect of theinvention the linear polysaccharide may be present in an amount of about18% of the total composition.

The film product of the invention may further include an additionalfilm-forming polymer. The additional film-forming polymer or polymersmay be a water soluble, water swellable, water miscible, waterdispersible, or a combination of one or more either water soluble, waterswellable, water miscible, or water dispersible polymers. The additionalfilm-forming polymer may include cellulose or a cellulose derivative.Specific examples of useful water soluble polymers include, but are notlimited to, polyethylene oxide (PEO), hydroxypropylmethyl cellulose(HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium aginate,polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum,arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinylcopolymers, starch, gelatin, and combinations thereof. Specific examplesof useful water miscible polymers or water dispersible polymers include,but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose,cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,hydroxypropylmethylcellulose acetate succinate (“HPMCA”), andcombinations thereof.

As used herein the phrase “water soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in water, anddesirably fully or predominantly soluble in water, or absorbs water.Polymers that absorb water are often referred to as being “waterswellable polymers.” The materials useful with the present invention maybe water soluble or water swellable at room temperature and othertemperatures, such as temperatures exceeding room temperature. Moreover,the materials may be water soluble or water swellable at pressures lessthan atmospheric pressure. Desirably, the water soluble polymers arewater soluble or water swellable having at least 20 percent by weightwater uptake. Water swellable polymers having a 25 or greater percent byweight water uptake are also useful. Films or dosage forms of thepresent invention formed from such water soluble polymers are desirablysufficiently water soluble to be dissolvable upon contact with bodilyfluids.

Other additional film-forming polymers useful for incorporation into thefilms of the present invention include biodegradable polymers,copolymers, block polymers and combinations thereof. Among the knownuseful polymers or polymer classes which meet the above criteria are:poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanones,polyoxalates, poly(α-esters), polyanhydrides, polyacetates,polycaprolactones, poly(orthoesters), polyamino acids,polyaminocarbonates, polyurethanes, polycarbonates, polyamides,poly(alkyl cyanoacrylates), and mixtures and copolymers thereof.Additional useful polymers include, stereopolymers of L- and D-lacticacid, copolymers of bis(p-carboxyphenoxy) propane acid and sebacic acid,sebacic acid copolymers, copolymers of caprolactone, poly(lacticacid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers ofpolyurethane and (poly(lactic acid), copolymers of polyurethane andpoly(lactic acid), copolymers of α-amino acids, copolymers of α-aminoacids and caproic acid, copolymers of α-benzyl glutamate andpolyethylene glycol, copolymers of succinate and poly(glycols),polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. Binary andternary systems are contemplated.

Other specific additional film-forming polymers useful include thosemarketed under the Medisorb and Biodel trademarks. The Medisorbmaterials are marketed by the Dupont Company of Wilmington, Del. and aregenerically identified as a “lactide/glycolide co-polymer” containing“propanoic acid, 2-hydroxy-polymer with hydroxy-polymer withhydroxyacetic acid.” Four such polymers include lactide/glycolide 100 L,believed to be 100% lactide having a melting point within the range of338°-347° F. (170°-175° C.); lactide/glycolide 100 L, believed to be100% glycolide having a melting point within the range of 437°-455° F.(225°-235° C.); lactide/glycolide 85/15, believed to be 85% lactide and15% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.); and lactide/glycolide 50/50, believed to be a copolymerof 50% lactide and 50% glycolide with a melting point within the rangeof 338°-347° F. (170°-175° C.). Lactide/glycolide co-polymers with otherratios of lactide to glycolide are also useful additional film-formingpolymers.

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

In aspects of the invention the additional film-forming polymer is anatural polymer.

In aspects of the invention the additional film-forming polymer ishydroxypropylmethylcellulose acetate succinate (“HPMCA”).

Preferred examples of useful additional film-forming polymers includehydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl ethylcellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulosephthalate, sodium alginate, polyethylene glycol, xanthan gum,tragancanth gum, locust bean gum, pea starch, carrageenan, taro rootgum, guar gum, acacia gum, arabic gum, starch, gelatin, and combinationsthereof.

The film products of the invention will have a total polymer contentthat includes the linear polysaccharide and any additional film-formingpolymer, if present.

The film product of the present invention further includes an activecomponent selected from pharmaceutical agents, medicaments, drugs,bioactive agents, cosmetic agents, and combinations thereof. The activecomponent may be present in any desired amount effective for theintended treatment. It is particularly desirable and an advantage of thepresent invention that the active component can be included at highloading. For example, the active component may be present in amounts upto about 65% by weight of the total composition. In aspects of theinvention the active component is present in amounts of about 40% orgreater, 45% or greater, 50% or greater, or 55% or greater, or 60% orgreater by weight of the total composition. In other aspects the activecomponent is present in an amount of about 0.01% to about 60% by weightof total composition.

Examples of useful drugs include ace-inhibitors, antianginal drugs,anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics,anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents,anti-diarrhea preparations, antidotes, anti-histamines,anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents,anti-manics, anti-nauseants, anti-stroke agents, anti-thyroidpreparations, anti-tumor drugs, anti-viral agents, acne drugs,alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs,anti-viral drugs, anabolic preparations, systemic and non-systemicanti-infective agents, anti-neoplastics, anti-parkinsonian agents,anti-rheumatic agents, appetite stimulants, biological responsemodifiers, blood modifiers, bone metabolism regulators, cardiovascularagents, central nervous system stimulates, cholinesterase inhibitors,contraceptives, decongestants, dietary supplements, dopamine receptoragonists, endometriosis management agents, enzymes, erectile dysfunctiontherapies, fertility agents, gastrointestinal agents, homeopathicremedies, hormones, hypercalcemia and hypocalcemia management agents,immunomodulators, immunosuppressives, migraine preparations, motionsickness treatments, muscle relaxants, obesity management agents,osteoporosis preparations, oxytocics, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sedatives, smoking cessation aids, sympatholytics,tremor preparations, urinary tract agents, vasodilators, laxatives,antacids, ion exchange resins, anti-pyretics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, psycho-tropics, stimulants, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thromboticdrugs, hypnotics, anti-emetics, anti-nauseants, neuromuscular drugs,hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations,diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs,erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics,DNA and genetic modifying drugs, and combinations thereof.

Erectile dysfunction therapies include, but are not limited to, drugsfor facilitating blood flow to the penis, and for effecting autonomicnervous activities, such as increasing parasympathetic (cholinergic) anddecreasing sympathetic (adrenergic) activities. Useful non-limiting oralphosphodiesterase Type V (PDE5) inhibitor drugs include sildenafils,such as Viagra®, tadalafils, such as Cialis®, vardenafils such asLavitra®, apomorphines, such as Uprima®, yohimbine hydrochlorides suchas Aphrodyne®, alprostadils such as Caverject®, phentolamines, udenafil,and avanafil. Other useful drugs work by increasing the nitric oxideproduction such as arginine, PNTX2-6 (Phoneutria nigrivente-spidertoxin) and forskolin and serotonin agonists like trazodone. Other usefulcompounds include those that that work to relax the corporal smoothmuscle tissue by inhibition of neutral endopeptidase, such assialorphin, which is an opiorphin. Also useful in the present inventionis the buccal absorption of stem cells. The use gene therapy agents arealso envisioned as a possible therapy for use in the present invention.

Among the useful sildenafils are sildenafil citrate, sildenafilhydrochloride, sildenafil resinate, sildenafil hydrogensulphate,sildenafil hemisulphate, sildenafil hemitartrate, sildenafil esylate,sildenafil fumarate, sildenafil lactate, sildenafil base, andcombinations thereof. A preferred sildenafil is sildenafil citrate.

When present the sildenafil may be included in an amount of about 10% toabout 65% by weight based on the total weight of the film product. Inaspects of the invention, a sildenafil may be present in amounts ofabout 20% to about 65% based on the total weight of the film product. Inaspects of the invention, a sildenafil may be present in amounts ofabout 40% to about 65% based on the total weight of the film product. Inother aspects of the invention, a sildenafil may be present in amountsof about 60% to about 65% based on the total weight of the film product.

In other aspects of the invention the film product is a dosage unit andthe sildenafil is present in the dosage unit in an amount equivalent toabout 5 to about 200 milligrams of sildenafil base; for example in anamount equivalent to about 25 to about 100 milligrams of sildenafilbase. In other aspects of the present invention, the film product is adosage unit and the sildenafil is present in the dosage unit in anamount equivalent to about 25, about 50, about 70, or about 100milligrams of sildenafil base.

In other aspects of the invention the film product the active componentis a pregabalin. Among the useful pregabalins are pregabalin acid,pregabalin hydrochloride, pregabalin hydrobromides, pregabalinhydrosulfate, pregabalin mandelate, pregabalin besylate, pregabalintosylate, and combinations thereof. A preferred pregabalin is pregabalinacid.

When present the pregabalin may be included in an amount of about 40% toabout 80% by weight based on the total weight of the film product. Inaspects of the invention, a pregabalin may be present in amounts ofabout 60% to about 75% based on the total weight of the film product. Inaspects of the invention, a pregabalin may be present in amounts ofabout 65% to about 75% based on the total weight of the film product.

In other aspects of the invention the film product is a dosage unit andthe pregabalin is present in the dosage unit in an amount equivalent toabout 5 to about 300 milligrams of pregabalin acid; for example in anamount equivalent to about 25 to about 150 milligrams of pregabalinacid. In other aspects of the present invention, the film product is adosage unit and the pregabalin is present in the dosage unit in anamount equivalent to about 150 milligrams of pregabalin acid.

In other aspects of the invention the film product the active componentis a tadalafil. When present the tadalafil may be included in an amountof about 5% to about 65% by weight based on the total weight of the filmproduct. In aspects of the invention, a tadalafil may be present inamounts of about 10% to about 65% based on the total weight of the filmproduct. In aspects of the invention, a tadalafil may be present inamounts of about 20% to about 65% based on the total weight of the filmproduct. In aspects of the invention, a tadalafil may be present inamounts of about 5% to about 20% based on the total weight of the filmproduct. In other aspects of the invention, a tadalafil may be presentin amounts of about 60% to about 65% based on the total weight of thefilm product.

In other aspects of the invention the film product is a dosage unit andthe tadalafil is present in the dosage unit in an amount of about 1 toabout 100 milligrams; for example in an amount of about 2 to about 50milligrams, in yet another example from about 5 to about 20 milligrams.In other aspects of the present invention, the film product is a dosageunit and the tadalafil is present in the dosage unit in an amount ofabout 5, about 10, or about 20 milligrams.

In aspects of the invention, the active component employed in thepresent invention may be incorporated into the film compositions of thepresent invention in a controlled release form. For example, particlesof drug may be coated with polymers such as ethyl cellulose orpolymethacrylate, commercially available under brand names such asAquacoat ECD and Eudragit E-100, respectively. Solutions of drug mayalso be absorbed on such polymer materials and incorporated into theinventive film compositions. Other components such as fats and waxes, aswell as sweeteners and/or flavors may also be employed in suchcontrolled release compositions.

The active component may be taste-masked prior to incorporation into thefilm composition, as set forth in the PCT Application No.PCT/US02/32594, entitled Uniform Films For Rapid Dissolve Dosage FormIncorporating Taste-Masking Compositions, based on U.S. ProvisionalApplication No. 60/414,276 of the same title, filed Sep. 27, 2002, theentire subject matter of which is incorporated by reference herein.

Examples of medicating active components contemplated for use in thepresent invention include antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂-antagonists.

Analgesics include opiates and opiate derivatives, such as oxycodone(commercially available as Oxycontin®); ibuprofen (commerciallyavailable as Motrin®, Advil®, Motrin Children's®, Motrin IBC), AdvilChildren's®, Motrin Infants'®, Motrin Junior®, Ibu-2®, Proprinal®,Ibu-200®, Midol Cramp Formula®, Bufen®, Motrin Migraine Pain®, Addaprin®and Haltran®), aspirin (commercially available as Empirin®, Ecotrin®,Genuine Bayer®, and Halfprin®), acetaminophen (commercially available asSilapap Infant's®, Silapap Children's®, Tylenol®, Tylenol Children's®,Tylenol Extra Strength®, Tylenol Infants' Original®, Tylenol Infants'®,Tylenol Arthritis®, T-Painol®, Q-Pap®, Cetafen®, Dolono®, Tycolene®,APAP® and Aminofen®), and combinations thereof that may optionallyinclude caffeine. Other pain relieving agents may be used in the presentinvention, including meperidine hydrochloride (commercially available asDemerol®), capsaicin (commercially available as Qutenza®), morphinesulfate and naltrexone hydrochloride (commercially available asEmbeda®), hydromorphone hydrochloride (commercially available asDilaudid®), propoxyphene napsylate and acetaminophen (commerciallyavailable as Darvocet-N®), Fentanyl (commercially available asDuragesic®, Onsolis®, and Fentora®), sodium hyaluronate (commerciallyavialble as Euflexxa®), adalimumab (commercially available as Humira®),sumatriptan succinate (commercially available as Imitrex®), fentanyliontophoretic (commercially available as Ionsys®), orphenadrine citrate(commercially available as Norgesic®), magnesium salicylate tetrahydrate(commercially available as Novasal®), oxymorphone hydrochloride(commercially available as Opana ER®), methocarbamol (commerciallyavailable as Robaxin®), carisoprodol (commercially available as Soma®),tramadol hydrochloride (commercially available as Ultracet® andUltram®), morphine sulfate (commercially available as MS Contin®),metaxalone (commercially available as Skelaxin®), oxycodonehydrochloride (commercially available as OxyContin®),acetaminophen/oxycodone hydrochloride (commercially available asPercocet®), oxycodone/aspirin (commercially available as Percodan®),hydrocodone bitartrate/acetaminophen (commercially available asVicodin®), hydrocodone bitartrate/ibuprofen (commercially available asVicoprofen®), nepafenac (commercially available as Nevanac®), andpregabalin (commercially available as Lyrica®).

The present invention may further include agents such as NSAIDs,including etodolac (commercially available as Lodine®), ketorolactromethamine (commercially available as Acular® or Acuvail®), naproxensodium (commercially available as Anaprox®, Naprosyn®), flurbiprofen(commercially available as Ansaid®), diclofenac sodium/misoprostol(commercially available as Arthrotec®), celecoxib (commerciallyavailable as Celebrex®), sulindac (commercially available as Clinoril®),oxaprozin (commercially available as Daypro®), piroxicam (commerciallyavailable as Feldene®), indomethacin (commercially available asIndocin®), meloxicam (commercially available as Mobic®), mefenamic acid(commercially available as Ponstel®), tolmetin sodium (commerciallyavailable as Tolectin®), choline magnesium trisalicylate (commerciallyavailable as Trilisate®), diclofenac sodium (commercially available asVoltaren®), diclofenac potassium (commercially available as Cambia® orZipsor®), and misoprostol (commercially available as Cytotec®). Opiatederivative, including opiate agonists and antagonists, such asbuprenorphine and naloxone are further examples of drugs for use in thepresent invention.

Other preferred active ingredients for use in the present inventioninclude anti-diarrheals such as loperamide (commercially available asImodium AD®, Kaodene®, Imperim®, Diamode®, QC Anti-Diarrheal®, HealthCare America Anti-Diarrheal®, Leader A-D®, and Imogen®), nitazoxanide(commercially available as Alinia®) and diphenoxylatehydrochloride/atropine sulfate (commercially available as Lomotil®),anti-histamines, anti-tussives, decongestants, vitamins, and breathfresheners/deodorizers. Common drugs used alone or in combination forcolds, pain, fever, cough, congestion, runny nose and allergies, such asacetaminophen, ibuprofen, chlorpheniramine maleate, dextromethorphan,dextromethorphan HBr, phenylephrine HCl, pseudoephedrine HCl,diphenhydramine and combinations thereof, such as dextromethophan HBrand phenylephrine HCl (available as Triaminic®) may be included in thefilm compositions of the present invention.

Other active agents useful in the present invention include, but are notlimited to alcohol dependence treatment, such as acamprosate calcium(commercially available as Campral®); Allergy treatment medications,such as promethazine hydrochloride (commercially available asPhenergan®), bepotastine besilate (commercially available as Bepreve®),hydrocodone polistirex/chlorpheniramine polistirex (commerciallyavailable as Tussionex®), cetirizine hydrochloride (commerciallyavailable as Zyrtec®), cetirizine hydrochloride/pseudoephedrinehydrochloride (commercially available as Zyrtec-D®), promethazinehydrochloride/codeine phosphate (commercially available as Phenergan®with Codeine), pemirolast (commercially available as Alamast®),fexofenadine hydrochloride (commercially available as Allegra®),meclizine hydrochloride (commercially available as Antivert®),azelastine hydrochloride (commercially available as Astelin®),nizatidine (commercially available as Axid®), desloratadine(commercially available as Clarinex®), cromolyn sodium (commerciallyavailable as Crolom®), epinastine hydrochloride (commercially availableas Elestat®), azelastine hydrochloride (commercially available asOptivar®), prednisolone sodium phosphate (commercially available asOrapred ODT®), olopatadine hydrochloride (commercially available asPatanol®), ketotifen fumarate (commercially available as Zaditor®), andmontelukast sodium (commercially available as Singulair®); andanti-histamines such as diphenhydramine HCl (available as Benadryl®),loratadine (available as Claritin®), astemizole (available asHismanal®), nabumetone (available as Relafen®), diphenydramine HCL(available as TheraFlu®) and clemastine (available as Tavist®).

Films of the present invention may further include Alzheimer's treatmentmedications, such as tacrine hydrochloride (commercially available asCognex®), galantamine (commercially available as Razadyne®), donepezilhydrochloride (commercially available as Aricept®), rivastigminetartrate (commercially available as Exelon®), caprylidene (commerciallyavailable as Axona®), and memantine (commercially available asNamenda®); anemia medication, such as cyanocobalamin (commerciallyavailable as Nascobal®) and ferumoxytol (commercially available asFeraheme®); anesthetics, such as antipyrine with benzocaine(commercially available as Auralgan®, Aurodex® and Auroto®); anginamedication, such as amlodipine besylate (commercially available asNorvasc®), nitroglycerin (commercially available as Nitro-Bid®,Nitro-Dur®, Nitrolingual®, Nitrostat®, Transderm-Nitro®), isosorbidemononitrate (commercially available as Imdur®), and isosorbide dinitrate(commercially available as Isordil®); anti-tussives such as guaifensin;anti-Alzheimer's agents, such as nicergoline; and Ca^(H)-antagonistssuch as nifedipine (commercially available as Procardia® and Adalat®).

Actives useful in the present invention may also includeanti-asthmatics, such as albuterol sulfate (commercially available asProventil®), ipratropium bromide (commercially available as Atrovent®),salmeterol xinafoate (commercially available as Serevent®), zafirlukast(commercially available as Accolate®), flunisolide (commerciallyavailable as AeroBid®), metaproterenol sulfate (commercially availableas Alupent®), albuterol inhalation (commercially available asVentolin®), terbutaline sulfate (commercially available as Brethine®),formoterol (commercially available as Foradil®), cromolyn sodium(commercially available as Intal®), levalbuterol hydrochloride(commercially available as Xopenex®), zileuton (commercially availableas Zyflo®), fluticasone propionate/salmeterol (commercially available asAdvair®), albuterol sulfate/triamcinolone acetonide (commerciallyavailable as Azmacort®), dimethylxanthine (commercially available asTheophylline®), and beclomethasone (commercially available asBeclovent®, Beconase®, Qvar®, Vancenase®, Vanceril®); angioedemamedication, such as C1 esterase Inhibitor (human) (commerciallyavailable as Berinert®) and ecallantide (commercially available asKalbitor®); and antibacterial medications, such astrimethoprim/sulfamethoxazole (commercially available as Bactrim®),mupirocin (commercially available as Bactroban®), metronidazole(commercially available as Flagyl®), sulfisoxazole acetyl (commerciallyavailable as Gantrisin®), bismuth subsalicylate andmetronidazole/tetracycline hydrochloride (commercially available asHelidac Therapy®), nitrofurantoin (commercially available asMacrodantin®), norfloxacin (commercially available as Noroxin®),erythromycin ethylsuccinate/Sulfisoxazole acetyl (commercially availableas Pediazole®), and levofloxacin (commercially available as Levaquin®).

The present invention may further include one or more antibiotics,including amoxicillin (commercially available as Amoxil®), ampicillin(commercially available as Omnipen®, Polycillin® and Principen®),amoxicillin/clavulanate potassium (commercially available asAugmentin®), moxifloxacin hydrochloride (commercially available asAvelox®), besifloxacin (commercially available as Besivance®),clarithromycin (commercially available as Biaxin®), ceftibuten(commercially available as Cedax®), cefuroxime axetil (commerciallyavailable as Ceftin®), cefprozil (commercially available as Cefzil®),ciprofloxacin hydrochloride (commercially available as Ciloxan® andCipro®), clindamycin phosphate (commercially available as Cleocin T®),doxycycline hyclate (commercially available as Doryx®), dirithromycin(commercially available as Dynabac®), erythromycin (commerciallyavailable as E.E.S.®, E-Mycin®, Eryc®, Ery-Tab®, Erythrocin®, and PCE®),erythromycin topical (commercially available as A/T/S®, Erycette®,T-Stat®), gemifloxacin (commercially available as Factive®), ofloxacin(commercially known as Ocuflox®, Floxin®), telithromycin (commerciallyavailable as Ketek®), lomefloxacin hydrochloride (commercially availableas Maxaquin®), minocycline hydrochloride (commercially available asMinocin®), fosfomycin tromethamine (commercially available as Monurol®),penicillin with potassium (commercially available as Penicillin VK®,Veetids®), trimethoprim (commercially available as Primsol®),ciprofloxacin hydrochloride (commercially available as Proquin XR®),rifampin, isoniazid and pyrazinamide (commercially available asRifater®), cefditoren (commercially available as Spectracef®), cefixime(commercially available as Suprax®), tetracycline (commerciallyavailable as Achromycin V® and Sumycin®), tobramycin (commerciallyavailable as Tobrex®), rifaximin (commercially available as Xifaxan®),azithromycin (commercially available as Zithromax®), azithromycinsuspension (commercially available as Zmax®), linezolid (commerciallyavailable as Zyvox®), benzoyl peroxide and clindamycin (commerciallyavailable as BenzaClin®), erythromycin and benzoyl peroxide(commercially available as Benzamycin®), dexamethasone (commerciallyavailable as Ozurdex®), ciprofloxacin and dexamethasone (commerciallyavailable as Ciprodex®), polymyxin B sulfate/neomycinsulfate/hydrocortisone (commercially available as Cortisporin®),colistin sulfate/neomycin sulfate/hydrocortisone acetate/thonzoniumbromide (commercially available as Cortisporin-TC Otic®), cephalexinhydrochloride (commercially available as Keflex®), cefdinir(commercially available as Omnicef®), and gatifloxacin (commerciallyavailable as Zymar®).

Other useful actives include cancer treatment medications, includingcyclophosphamide (commercially available as Cytoxan®), methotrexate(commercially available as Rheumatrex® and Trexal®), tamoxifen citrate(commercially available as Nolvadex®), bevacizumab (commerciallyavailable as Avastin®), everolimus (commercially available asAfinitor®), pazopanib (commercially available as Votrient®), andanastrozole (commercially available as Arimidex®); leukemia treatment,such as ofatumumab (commercially available as Arzerra®); anti-thromboticdrugs, such as antithrombin recombinant lyophilized powder (commerciallyavailable as Atryn®), prasugrel (commercially available as Efient®);anti-coagulants, such as aspirin with extended-release dipyridamole(commercially available as Aggrenox®), warfarin sodium (commerciallyavailable as Coumadin®), dipyridamole (commercially available asPersantine®), dalteparin (commercially available as Fragmin®),danaparoid (commercially available as Orgaran®), enoxaparin(commercially available as Lovenox®), heparin (commercially available asHep-Lock, Hep-Pak, Hep-Pak CVC, Heparin Lock Flush), tinzaparin(commercially available as Innohep®), and clopidogrel bisulfate(commercially available as Plavix®); antiemetics, such as granisetronhydrochloride (commercially available as Kytril®) and nabilone(commercially available as Cesamet®), trimethobenzamide hydrochloride(commercially available as Tigan®), and ondansetron hydrochloride(commercially available as Zofran®); anti-fungal treatment, such asketoconazole (commercially available as Nizoral®), posaconazole(commercially available as Noxafil®), ciclopirox (commercially availableas Penlac®), griseofulvin (commercially available as Gris-PEG®),oxiconazole nitrate (commercially available as Oxistat®), fluconazole(commercially available as Diflucan®), sertaconazole nitrate(commercially available as Ertaczo®), terbinafine hydrochloride(commercially available as Lamisil®), ciclopirox (commercially availableas Loprox®), nystatin/triamcinolone acetonide (commercially available asMycolog-II®), econazole nitrate (commercially available as Spectazole®),itraconazole (commercially available as Sporanox®), and terconazole(commercially available as Terazol®).

Active agents may further include anti-inflammatory medications, such ashydroxychloroquine sulfate (commercially available as Plaquenil®),fluticasone propionate (commercially available as Cutivate®),canakinumab (commercially available as Llaris®), amcinonide(commercially available as Cyclocort®), methylprednisolone (commerciallyavailable as Medrol®), budesonide (commercially available as EntocortEC®), anakinra (commercially available as Kineret®), diflorasonediacetate (commercially available as Psorcon®), and etanercept(commercially available as Enbrel®); antispasmodic medication, such asphenobarbital/hyoscyamine sulfate/atropine sulfate/scopolaminehydrobromide (commercially available as Donnatal®); antiviral treatment,such as oseltamivir phosphate (commercially available as Tamiflu®);anti-parasites medication, including tinidazole (commercially availableas Tindamax®); appetite treatment mediations, such as megestrol acetate(commercially available as Megace ES®), phentermine hydrochloride(commercially available as Adipex-P®), and diethylpropion hydrochloride(commercially available as Tenuate®); arthritis medications, includingleflunomide (commercially available as Arava®), certolizumab pegol(commercially available as Cimzia®), diclofenac sodium (commerciallyavailable as Pennsaid®), golimumab (commercially available as Simponi®),and tocilizumab (commercially available as Actemra®); bladder controlmedication, such as trospium chloride (commercially available asSanctura®), desmopressin acetate (commercially available as DDAVP®),tolterodine tartrate (commercially available as Detrol®), oxybutyninchloride (commercially available as Ditropan® or Gelnique®), darifenacin(commercially available as Enablex®), and solifenacin succinate(commercially available as VESlcare®); blood vessel constrictors, suchas methylergonovine maleate (commercially available as Methergine®);plasma uric managers, such as rasburicase (commercially available asElitek®); iron deficiency anemia medications, such as ferumoxytol(commercially available as Feraheme®); lymphoma medications, such aspralatrexate (commercially available as Folotyn®), romidepsin(commercially available as Isodax®); malaria medication, such asartemether/lumefantrine (commercially available as Coartem®);hyponatremia medication, such as tolvatpan (commercially available asSamsca®); medication for treatment of von Willebrand disease(commercially available as Wilate®); anti-hypertension medications, suchas treprostinil (commercially available as Tyvaso®), tadalafil(commercially available as Adcirca®); cholesterol lowering medication,including paricalcitol (commercially available as Altocor®),pitavastatin (commercially available as Livalo®), lovastatin, niacin(commercially available as Advicor®), colestipol hydrochloride(commercially available as Colestid®), rosuvastatin calcium(commercially available as Crestor®), fluvastatin sodium (commerciallyavailable as Lescol®), atorvastatin calcium (commercially available asLipitor®), lovastatin (commercially available as Mevacor®), niacin(commercially available as Niaspan®), pravastatin sodium (commerciallyavailable as Pravachol®), pavastatin sodium with buffered aspirin(commercially available as Pravigard PAC®), cholestyramine (commerciallyavailable as Questran®), simvastatin and niacin (commercially availableas Simcor®), atenolol, chlorthalidone (commercially available asTenoretic®), atenolol (commercially available as Tenormin®), fenofibrate(commercially available as Tricor®), fenofibrate (commercially availableas Triglide®), ezetimibe/simvastatin (commercially available asVytorin®), colesevelam (commercially available as WelChol®), bisoprololfumarate (commercially available as Zebeta®), ezetimibe (commerciallyavailable as Zetia®), bisoprolol fumarate/hydrochlorothiazide(commercially available as Ziac®), and simvastatin (commerciallyavailable as Zocor®).

The actives included herein may also include chronic kidney diseasemedication, such as paricalcitol (commercially available as Zemplar®);contraceptive agents, including etonogestrel (commercially available asImplanon®), norethindrone acetate, ethinyl estradiol (commerciallyavailable as Loestrin 24 FE®), ethinyl estradiol, norelgestromin(commercially available as Ortho Evra®), levonorgestrel (commerciallyavailable as Plan B®), levonorgestrel and ethinyl estradiol(commercially available as Preven®), levonorgestrel, ethinyl estradiol(commercially available as Seasonique®), and medroxyprogesterone acetate(commercially available as Depo-Provera®); COPD medication, such asarformoterol tartrate (commercially available as Brovana®) andipratropium bromide, albuterol sulfate (commercially available asCombivent®); cough suppressants, including benzonatate (commerciallyavailable as Tessalon®), guaifenesin, codeine phosphate (commerciallyavailable as Tussi-Organidin NR®), and acetaminophen, codeine phosphate(commercially available as Tylenol with Codeine®); medication for thetreatment of diabetes, including pioglitazone hydrochloride, metforminhydrochloride (commercially available as ACTOplus met®), bromocriptinemesylate (commercially available as Cycloset®), liraglutide(commercially available as Victoza®), saxagliptin (commerciallyavailable as Onglyza®), pioglitazone hydrochloride (commerciallyavailable as Actos®), glimepiride (commercially available as Amaryl®),rosiglitazone maleate, metformin hydrochloride (commercially availableas Avandamet®), rosiglitazone maleate (commercially available asAvandaryl®), rosiglitazone maleate (commercially available as Avandia®),exenatide (commercially available as Byetta®), chlorpropamide(commercially available as Diabinese®), pioglitazone hydrochloride,glimepiride (commercially available as Duetact®), metforminhydrochloride (commercially available as Glucophage®), glipizide(commercially available as Glucotrol®), glyburide, metformin(commercially available as Glucovance®), metformin hydrochloride(commercially available as Glumetza®), sitagliptin (commerciallyavailable as Januvia®), detemir (commercially available as Levemir®),glipizide, metformin hydrochloride (commercially available asMetaglip®), glyburide (commercially available as Micronase®),repaglinide (commercially available as Prandin®), acarbose (commerciallyavailable as Precose®), nateglinide (commercially available asStarlix®), pramlintide acetate (commercially available as Symlin®), andtolazamide (commercially available as Tolinase®).

Other useful agents of the present invention may include digestiveagents, such as sulfasalazine (commercially available as Azulfidine®),rabeprazole sodium (commercially available as AcipHex®), lubiprostone(commercially available as Amitiza®), dicyclomine hydrochloride(commercially available as Bentyl®), sucralfate (commercially availableas Carafate®), lactulose (commercially available as Chronulac®),docusate (commercially available as Colace®), balsalazide disodium(commercially available as Colazal®), losartan potassium (commerciallyavailable as Cozaar®), olsalazine sodium (commercially available asDipentum®), chlordiazepoxide hydrochloride, clidinium bromide(commercially available as Librax®), esomeprazole magnesium(commercially available as Nexium®), famotidine (commercially availableas Pepcid®), lansoprazole (commercially available as Prevacid®),lansoprazole and naproxen (commercially available as PrevacidNapraPAC®), amoxicillin/clarithromycin/lansoprazole (commerciallyavailable as Prevpac®), omeprazole (commercially available asPrilosec®), pantoprazole sodium (commercially available as Protonix®),metoclopramide hydrochloride (commercially available as Reglan® orMetozolv®), cimetidine (commercially available as Tagamet®), ranitidinehydrochloride (commercially available as Zantac®), and omeprazole,sodium bicarbonate (commercially available as Zegerid®); diuretics,including spironolactone, hydrochlorothiazide (commercially available asAldactazide®), spironolactone (commercially available as Aldactone®).bumetanide (commercially available as Bumex®), torsemide (commerciallyavailable as Demadex®), chlorothiazide (commercially available asDiuril®), furosemide (commercially available as Lasix®), metolazone(commercially available as Zaroxolyn®), and hydrochlorothiazide,triamterene (commercially available as Dyazide®).

Agents useful herein may also include treatment for emphysema, such astiotropium bromide (commercially available as Spiriva®); fibromyalgiamedication, such as milnacipran hydrochloride (commercially available asSavella®); medication for the treatment of gout, such as colchicine(commercially available as Colcrys®), and febuxostat (commerciallyavailable as Uloric®); enema treatments, including aminosalicylic acid(commercially available as Mesalamine® and Rowasa®); epilepsymedications, including valproic acid (commercially available asDepakene®), felbamate (commercially available as Felbatol®), lamotrigine(commercially available as Lamictal®), primidone (commercially availableas Mysoline®), oxcarbazepine (commercially available as Trileptal®),zonisamide(commercially available as Zonegran®), levetiracetam(commercially available as Keppra®), and phenytoin sodium (commerciallyavailable as Dilantin®).

Agents useful herein may further include eye medications and treatment,such as dipivefrin hydrochloride (commercially available as Propine®),valganciclovir (commercially available as Valcyte®), ganciclovirophthalmic gel (commercially available as Zirgan®); bepotastine besilate(commercially available as Bepreve®), besifloxacin (commerciallyavailable as Besivance®), bromfenac (commercially available as Xibrom®),fluorometholone (commercially available as FML®), pilocarpinehydrochloride (commercially available as Pilocar®), cyclosporine(commercially available as Restasis®), brimonidine tartrate(commercially available as Alphagan P®), dorzolamidehydrochloride/timolol maleate (commercially available as Cosopt®),bimatoprost (commercially available as Lumigan®), timolol maleate(available as Timoptic®), travoprost (commercially available asTravatan®), latanoprost (commercially available as Xalatan®),echothiophate iodide (commercially available as Phospholine Iodide®),and ranibizumab (commercially available as Lucentis®); fluidcontrollers, such as acetazolamide (commercially available as Diamox®);gallstone medications, including ursodiol (commercially available asActigall®); medication for the treatment of gingivitis, includingchlorhexidine gluconate (commercially available as Peridex®); headachemedications, including butalbital/codeine phosphate/aspirin/caffeine(commercially available as Fiornal® with Codeine), naratriptanhydrochloride (commercially available as Amerge®), almotriptan(commercially available as Axert®), ergotamine tartrate/caffeine(commercially available as Cafergot®), butalbital/acetaminophen/caffeine(commercially available as Fioricet®), butalbital/aspirin/caffeine(commercially available as Fiorinal®), frovatriptan succinate(commercially available as Frova®), rizatriptan benzoate (commerciallyavailable as Maxalt®), isometheptenemucate/dichloralphenazone/acetaminophen (commercially available asMidrin®), dihydroergotamine mesylate (commercially available asMigranal®), eletriptan hydrobromide (commercially available as Relpax®),and zolmitriptan (commercially available as Zomig®); influenzamedication, such as haemophilus b conjugate vaccine; tetanus toxoidconjugate (commercially available as Hiberix®); and heart treatments,including quinidine sulfate, isosorbide dinitrate/hydralazinehydrochloride (commercially available as BiDil®), digoxin (commerciallyavailable as Lanoxin®), flecainide acetate (commercially available asTambocor®), mexiletine hydrochloride (commercially available asMexitil®), disopyramide phosphate (commercially available as Norpace®),procainamide hydrochloride (commercially available as Procanbid®), andpropafenone (commercially available as Rythmol®).

Other useful agents include hepatitis treatments, including entecavir(commercially available as Baraclude®), hepatitis B immune globulin(commercially available as HepaGam B®), andcopegus/rebetol/ribasphere/vilona/virazole (commercially available asRibavirin®); herpes treatments, including valacyclovir hydrochloride(commercially available as Valtrex®), penciclovir (commerciallyavailable as Denavir®), acyclovir (commercially available as Zovirax®),and famciclovir (commercially available as Famvir®); treatment for highblood pressure, including enalaprilat (available as Vasotec®), captopril(available as Capoten®) and lisinopril (available as Zestril®),verapamil hydrochloride (available as Calan®), ramipril (commerciallyavailable as Altace®), olmesartan medoxomil (commercially available asBenicar®), amlodipine/atorvastatin (commercially available as Caduet®),nicardipine hydrochloride (commercially available as Cardene®),diltiazem hydrochloride (commercially available as Cardizem®), quinaprilhydrochloride (commercially available as Accupril®), quinaprilhydrochloride/hydrochlorothiazide (commercially available asAccuretic®), perindopril erbumine (commercially available as Aceon®),candesartan cilexetil (commercially available as Atacand®), candesartancilexetil/hydrochlorothiazide (commercially available as Atacand HCT®),irbesartan/hydrochlorothiazide (commercially available as Avalide®),irbesartan (commercially available as Avapro®), amlodipinebesylate/olmesartan medoxomil (commercially available as Azor®),levobunolol hydrochloride (commercially available as Betagan®),betaxolol hydrochloride (commercially available as Betoptic®), nebivolol(commercially available as Bystolic®), captopril/hydrochlorothiazide(commercially available as Capozide®), doxazosin mesylate (commerciallyavailable as Cardura®), clonidine hydrochloride (commercially availableas Catapres®), carvedilol (commercially available as Coreg®), nadolol(commercially available as Corgard®), nadolol/bendroflumethiazide(commercially available as Corzide®), valsartan (commercially availableas Diovan®), isradipine (commercially available as DynaCirc®), Guanabenzacetate. (commercially available as Wytensin®), Guanfacine hydrochloride(commercially available as Tenex® or Intuniv®), losartanpotassium/hydrochlorothiazide (commercially available as Hyzaar®),propranolol hydrochloride (commercially available as Indera®),propranolol hydrochloride/hydrochlorothiazide (commercially available asInderide®), eplerenone (commercially available as Inspra®), ambrisentan(commercially available as Letairis®), enalapril maleate/felodipine(commercially available as Lexxel®), metoprolol tartrate (commerciallyavailable as Lopressor®), benazepril hydrochloride (commerciallyavailable as Lotensin®), benazepril hydrochloride/hydrochlorothiazide(commercially available as Lotensin HCT®), amlodipine/benazeprilhydrochloride (commercially available as Lotrel®), indapamide(commercially available as Lozol®), trandolapril (commercially availableas Mavik®), telmisartan (commercially available as Micardis®),telmisartan/hydrochlorothiazide (commercially available as MicardisHCT®), prazosin hydrochloride (commercially available as Minipress®),amiloride, hydrochlorothiazide (commercially available as Moduretic®),fosinopril sodium (commercially available as ZZXT Monopril®), fosinoprilsodium/hydrochlorothiazide (commercially available as Monopril-HCT®),pindolol (commercially available as Visken®), felodipine (commerciallyavailable as Plendil®), sildenafil citrate (commercially available asRevatio®), Nisoldipine (commercially available as Sular®),trandolapril/verapamil hydrochloride (commercially available as Tarka®),aliskiren (commercially available as Tekturna®), eprosartan mesylate(commercially available as Teveten®), eprosartanmesylate/hydrochlorothiazide (commercially available as Teveten HCT®),moexipril hydrochloride/hydrochlorothiazide (commercially available asUniretic®), moexipril hydrochloride (commercially available asUnivasc®), enalapril maleate/hydrochlorothiazide (commercially availableas Vaseretic®), and lisinopril/hydrochlorothiazide (commerciallyavailable as Zestoretic®).

The present invention may include agents useful in the medication forthe treatment of HIV/AIDS, such as amprenavir (commercially available asAgenerase®), tipranavir (commercially available as Aptivus®),efavirenz/emtricitabine/tenofovir (commercially available as Atripla®),lamivudine/zidovudine (commercially available as Combivir®), indinavirsulfate (commercially available as Crixivan®), lamivudine (commerciallyavailable as Epivir®), saquinavir (commercially available asFortovase®), zalcitabine (commercially available as Hivid®),lopinavir/ritonavir (commercially available as Kaletra®), fosamprenavircalcium (commercially available as Lexiva®), ritonavir (commerciallyavailable as Norvir®), zidovudine (commercially available as Retrovir®),atazanavir sulfate (commercially available as Reyataz®), efavirenz(commercially available as Sustiva®), abacavir/lamivudine/zidovudine(commercially available as Trizivir®), didanosine (commerciallyavailable as Videx®), nelfinavir mesylate (commercially available asViracept®), nevirapine (commercially available as Viramune®), tenofovirdisoproxil fumarate (commercially available as Viread®), stavudine(commercially available as Zerit®), and abacavir sulfate (commerciallyavailable as Ziagen®); homocysteiene removers, including betaineanhydrous (commercially available as Cystadane®); medications, such asinsulin (commercially available as Apidra®, Humalog®, Humulin®, Iletin®,and Novolin®); and HPV treatment, such as Human papillomavirus vaccine(commercially available as Gardasil®) or human papillomavirus bivalent(commercially available as Cervarix®); immunosuppressants, includingcyclosporine (commercially available as Gengraf®, Neoral®, Sandimmune®,and Apo-Cyclosporine®).

Agents useful in the present invention may further include prolactininhibitors, such as bromocriptine mesylate (commercially available asParlodel®); medications for aiding in stress tests, such as regadenoson(commercially available as Lexiscan®); baldness medication, includingfinasteride (commercially available as Propecia® and Proscar®);pancreatitis treatment, such as gemfibrozil (commercially available asLopid®); hormone medications, such as norethindrone acetate/ethinylestradiol (commercially available as femHRT®), goserelin acetate(commercially available as Zoladex®), progesterone gel (commerciallyavailable as Prochieve®), progesterone (commercially available asPrometrium®), calcitonin-salmon (commercially available as Miacalcin®),calcitriol (commercially available as Rocaltrol®), synthroid(commercially available as Levothroid®, Levoxyl®, Unithroid®),testosterone (commercially available as Testopel®, Androderm®,Testoderm®, and AndroGel®); menopause medication, such asestradiol/norethindrone acetate (commercially available as Activella®),drospirenone/estradiol (commercially available as Angeliq®),estradiol/levonorgestrel (commercially available as Climara Pro®),estradiol/norethindrone acetate (commercially available as CombiPatch®),estradiol (commercially available as Estrasorb®, Vagifem® andEstroGel®), esterified estrogens and methyltestosterone (commerciallyavailable as Estratest®), estrogen (commercially available as Alora®,Climara®, Esclim®, Estraderm®, Vivelle®, Vivelle-Dot®), estropipate(commercially available as Ogen®), conjugated estrogens (commerciallyavailable as Premarin®), and medroxyprogesterone acetate (commerciallyavailable as Provera®); menstrual medications, including leuprolideacetate (commercially available as Lupron Depot), tranexamic acid(commercially available as Lysteda®), and norethindrone acetate(commercially available as Aygestin®); and muscle relaxants, includingcyclobenzaprine hydrochloride (commercially available as Flexeril®),tizanidine (commercially available as Zanaflex®), and hyoscyaminesulfate (commercially available as Levsin®).

Agents useful herein may also include osteoporosis medications,including ibrandronate sodium (commercially available as Boniva®),risedronate (commercially available as Actonel®), raloxifenehydrochloride (commercially available as Evista®, Fortical®), andalendronate sodium (commercially available as Fosamax®); ovulationenhancers, including clomiphene citrate (commercially available asSerophene®, Clomid®, Serophene®); Paget's disease treatment, such asetidronate disodium (commercially available as Didronel®); pancreaticenzyme deficiency medications, such as pancrelipase (commerciallyavailable as Pancrease® or Zenpep®); medication for the treatment ofParkinson's disease, such as pramipexole dihydrochloride (commerciallyavailable as Mirapex®), ropinirole hydrochloride (commercially availableas Requip®), carbidopa/levodopa (commercially available as Sinemet CR®),carbidopa/levodopa/entacapone (commercially available as Stalevo®),selegiline hydrochloride (commercially available as Zelapar®),rasagiline (commercially available as Azilect®), entacapone(commercially available as Comtan®), and selegiline hydrochloride(commercially available as Eldepryl®); multiple sclerosis medication,such as dalfampridine (commercially available as Ampyra®) and interferonbeta-Ib (commercially available as Extavia®); prostate medication,including flutamide (commercially available as Eulexin®), nilutamide(commercially available as Nilandron®), dutasteride (commerciallyavailable as Avodart®), tamsulosin hydrochloride (commercially availableas Flomax®), terazosin hydrochloride (commercially available asHytrin®), and alfuzosin hydrochloride (commercially available asUroXatral®).

Films of the present invention may further include psychiatricmedications, including alprazolam (available as Niravam®, Xanax®),clozopin (available as Clozaril®), haloperidol (available as Haldol®),fluoxetine hydrochloride (available as Prozac®), sertralinehydrochloride (available as Zoloft®), asenapine (commercially availableas Saphris®), iloperidone (commercially available as Fanapt®), paroxtinehydrochloride (available as Paxil®), aripiprazole (commercially aavialbeas Abilify®), guanfacine (commercially available as Intuniv®),Amphetamines and methamphetamines (commercially available as Adderall®and Desoxyn®), clomipramine hydrochloride (commercially available asAnafranil®), Buspirone hydrochloride (commercially available asBuSpar®), citalopram hydrobromide (commercially available as Celexa®),duloxetine hydrochloride (commercially available as Cymbalta®),methylphenidate (commercially available as Ritalin, Daytrana®),divalproex sodium (Valproic acid) (commercially available as Depakote®),dextroamphetamine sulfate (commercially available as Dexedrine®),venlafaxine hydrochloride (commercially available as Effexor®),selegiline (commercially available as Emsam®), carbamazepine(commercially available as Equetro®), lithium carbonate (commerciallyavailable as Eskalith®), fluvoxamine maleate/dexmethylphenidatehydrochloride (commercially available as Focalin®), ziprasidonehydrochloride (commercially available as Geodon®), ergoloid mesylates(commercially available as Hydergine®), escitalopram oxalate(commercially available as Lexapro®), chlordiazepoxide (commerciallyavailable as Librium®), molindone hydrochloride (commercially availableas Moban®), phenelzine sulfate (commercially available as Nardil®),thiothixene (commercially available as Navane®), desipraminehydrochloride (commercially available as Norpramin®), benzodiazepines(such as those available as Oxazepam®), nortriptyline hydrochloride(commercially available as Pamelor®), tranylcypromine sulfate(commercially available as Parnate®), prochlorperazine, mirtazapine(commercially available as Remeron®), risperidone (commerciallyavailable as Risperdal®), quetiapine fumarate (commercially available asSeroquel®), doxepin hydrochloride (commercially available as Sinequan®),atomoxetine hydrochloride (commercially available as Strattera®),trimipramine maleate (commercially available as Surmontil®),olanzapine/fluoxetine hydrochloride (commercially available asSymbyax®), imipramine hydrochloride (commercially available asTofranil®), protriptyline hydrochloride (commercially available asVivactil®), bupropion hydrochloride (commercially available asWellbutrin®, Wellbutrin SR®, and Wellbutrin XR®), and olanzapine(commercially available as Zyprexa®).

Agents useful herein may also include uric acid reduction treatment,including allopurinol (commercially available as Zyloprim®); seizuremedications, including gabapentin (commercially available asNeurontin®), ethotoin (commercially available as Peganone®), vigabatrin(commercially available as Sabril®), and topiramate (commerciallyavailable as Topamax®); treatment for shingles, such as zoster vaccinelive (commercially available as Zostavax®); skin care medications,including calcipotriene (commercially available as Dovonex®),ustekinumab (commercially available as Stelara®), televancin(commercially available as Vibativ®), isotretinoin (commerciallyavailable as Accutane®), hydrocortisone/iodoquinol (commerciallyavailable as Alcortin®), sulfacetamide sodium/sulfur (commerciallyavailable as Avar®), azelaic acid (commercially available as Azelex®,Finacea®), benzoyl peroxide (commercially available as Desquam-E®),adapalene (commercially available as Differin®), fluorouracil(commercially available as Efudex®), pimecrolimus (commerciallyavailable as Elidel®), topical erythromycin (commercially available asA/T/S®, Erycette®, T-Stat®), hydrocortisone (commercially available asCetacort®, Hytone®, Nutracort®), metronidazole (commercially availableas MetroGel®), doxycycline (commercially available as Oracea®),tretinoin (commercially available as Retin-A® and Renova®),mequinol/tretinoin (commercially available as Solage®), acitretin(commercially available as Soriatane®), calcipotrienehydrate/betamethasone dipropionate (commercially available asTaclonex®), tazarotene (commercially available as Tazorac®),fluocinonide (commercially available as Vanos®), desonide (commerciallyavailable as Verdeso®), miconazole nitrate/Zinc oxide (commerciallyavailable as Vusion®), ketoconazole (commercially available asXolegel®), and efalizumab (commercially available as Raptiva®).

Other agents useful herein may include Sleep disorder medications,including zaleplon (available as Sonata®), eszopiclone (available asLunesta®), zolpidem tartrate (commercially available as Ambien®, AmbienCR®, Edluar®), lorazepam (commercially available as Ativan®), flurazepamhydrochloride (commercially available as Dalmane®), triazolam(commercially available as Halcion®), clonazepam (commercially availableas Klonopin®), barbituates, such as Phenobarbital®), Modafinil(commercially available as Provigil®), temazepam (commercially availableas Restoril®), ramelteon (commercially available as Rozerem®),clorazepate dipotassium (commercially available as Tranxene®), diazepam(commercially available as Valium®), quazepam (commercially available asDoral®), and estazolam (commercially available as ProSom®); smokingcessation medications, such as varenicline (commercially available asChantix®), nicotine, such as Nicotrol®, and bupropion hydrochloride(commercially available as Zyban®); and steroids, includingalclometasone dipropionate (commercially available as Aclovate®),betamethasone dipropionate (commercially available as Diprolene®),mometasone furoate (commercially available as Elocon®), fluticasone(commercially available as Flonase®, Flovent®, Flovent Diskus®, FloventRotadisk®), fluocinonide (commercially available as Lidex®), mometasonefuroate monohydrate (commercially available as Nasonex®), desoximetasone(commercially available as Topicort®), clotrimazole/betamethasonedipropionate (commercially available as Lotrisone®), prednisoloneacetate (commercially available as Pred Forte®, Prednisone®, BudesonidePulmicort®, Rhinocort Aqua®), prednisolone sodium phosphate(commercially available as Pediapred®), desonide (commercially availableas Tridesilon®), and halobetasol propionate (commercially available asUltravate®).

Films of the present invention may further include agents useful forthyroid disease treatment, such as hormones TC and TD (commerciallyavailable as Armour Thyroid®); potassium deficiency treatment, includingpotassium chloride (commercially available as Micro-KC)); triglyceridesregulators, including omega-3-acid ethyl esters (commercially availableas Omacor®); urinary medication, such as phenazopyridine hydrochloride(commercially available as Pyridium®) and methenamine, methyleneblue/phenyl salicylate/benzoic acid/atropine sulfate/hyoscyamine(commercially available as Urised®); prenatal vitamins (commerciallyavailable as Advanced Natalcare®, Materna®, Natalins®, PrenateAdvance®); weight control medication, including orlistat (commerciallyavailable as Xenical®) and sibutramine hydrochloride (commerciallyavailable as Meridia®).

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidine, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium carbonate, calcium phosphate, citrate ion (acidor salt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono-ordibasic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts.

The pharmaceutically active agents employed in the present invention mayinclude allergens or antigens, such as, but not limited to, plantpollens from grasses, trees, or ragweed; animal danders, which are tinyscales shed from the skin and hair of cats and other furred animals;insects, such as house dust mites, bees, and wasps; and drugs, such aspenicillin

An anti-oxidant may also be added to the film to prevent the degradationof an active, especially where the active is oxidation sensitive, forexample, photosensitive.

Cosmetic active agents may include breath freshening compounds such asd-menthol and 1-menthol, other flavors; such as mint, cherry, lemonlime, mixed berry, grapefruit, eucalyptol, methyl salicylate, andthymol, or fragrances, especially those used for oral hygiene, as wellas actives used in dental and oral cleansing such as quaternary ammoniumbases, hydrogen peroxide, moisturizers, and vitamin E The effect offlavors may be enhanced using flavor enhancers like tartaric acid,vanillin, or the like.

Also color additives can be used in preparing the films. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments include, for example the oxides of iron or titanium. The oxidesof iron or titanium are preferably added in concentrations ranging fromabout 0.001 to about 10%, and more preferably in amounts of about 0.5 toabout 3%, based on the weight of all the components.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

The films containing flavorings may be added to provide a hot or coldflavored drink or soup. These flavorings include, without limitation,tea and soup flavorings such as beef and chicken.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), sucrose, dextrose, invert sugar, fructose, andcombinations thereof; saccharin and its various salts such as the sodiumsalt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,maltitol, xylitol, and the like. Also contemplated are hydrogenatedstarch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

Plasticizers useful in the in the films of the invention include, forexample, xylitol, polyalkylene oxides, such as polyethylene glycols,polypropylene glycols, polyethylene-propylene glycols; organicplasticizers with low molecular weights, such as glycerol (glycerin),glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate,cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate,triethyl citrate, tributyl citrate, and the like.

When using linear polysaccharides, such as pullulan, in making oralsoluble films there is a fine line between tackiness and brittlenessevidenced much more so with Pullulan than with other polymer systems. Anarrow selection of plasticizers exists that result in flexible filmthat is not tacky, brittle, or fracture sensitive. There is also apreferred selection and combination of plasticizers that stand out forproducing oral soluble films (OSF) that pass all subjective tests forhigh speed film production and packaging and storage.

Such combinations of plasticizers may result in the ability to loadhigher amounts of active pharmaceutical ingredient per film and stillallow the films to dissolve at a faster Partial Immersion Dissolution(PID) when compared to a traditional type of OSF polymer formulations.Moreover, among the narrow plasticizer selection there is a preferredrange of plasticizer amounts.

Accordingly, the plasticizers useful in the present invention includexylitol, glycerin, and combination thereof. The plasticizer is presentin an amount of about 10% to about 45% by weight based on the combinedweight of the plasticizer and the total polymer content. In an aspect ofthe invention the plasticizer is present in an amount of about 10% toabout 40% by weight based on the combined weight of the plasticizer andthe total polymer content. In another aspect of the invention theplasticizer is present in an amount of about 15% to about 22.5% byweight based on the combined weight of the plasticizer and the totalpolymer content. In yet another aspect of the invention the plasticizeris present in an amount of about 18% to about 21% by weight based on thecombined weight of the plasticizer and the total polymer content.

As discussed above, previous attempts to produce useful pullulan filmhave used water as a plasticizer with and without starch, xanthan andgellan gum. However, these films are dried with relatively high amountsof water left in the film, as much as 5-10%, which can make them abreeding ground for microbial growth in some situations. Moreover, water(residual moisture in the film) tends to evaporate from suchformulations over time and the loss of the plasticizer (water) leads tobrittleness of the finished film as the film ages.

In aspects of the invention, the film product is substantially free ofwater. For example, the water content of the film product of theinvention is about 10% or less by weight, preferably about 5% or less byweight of the total weight of the film product. In an aspect of theinvention, the water content of the film product is about 4% or less byweight, or about 2% or less by weight, based on the total weight of thefilm product.

The film product of the invention may further include an acid. In anaspect of the invention the acid is a water soluble carboxylic acid.Examples of useful acids include citric acid, formic acid, acetic acid,propionic acid, ascorbic acid, lactic acid, malic acid, tartaric acid,and combinations thereof. When present in the film product the acid isin an amount of about 0.1% to about 10% by weight based on the totalweight of the film product. In an aspect of the invention the acid ispresent in an amount of about 2 to about 6% by weight, or about 5% byweight, based on the total weight of the film product. In an aspect ofthe invention the acid is citric acid.

In an aspect of the invention the plasticizer is a xylitol, which ispresent in an amount of about 10% to about 45% by weight based on thecombined weight of the xylitol and the total polymer content. In anotheraspect of the invention the plasticizer xylitol, which is present in anamount of about 20 to about 40% by weight based on the combined weightof the xylitol and the total polymer content.

In an aspect of the invention the plasticizer is a glycerin, which ispresent in an amount of about 15% to about 22.5% by weight based on thecombined weight of the glycerin and the total polymer content. Inanother aspect of the invention the plasticizer glycerin, which ispresent in an amount of about 18 to about 21% by weight based on thecombined weight of the glycerin and the total polymer content.

In an aspect of the invention the plasticizer is a combination ofxylitol and glycerin, wherein 1) the amount of glycerin is about equalto or less than the amount of xylitol by weight; and 2) the combinationof xylitol and glycerin is present in an amount of about 40% or less byweight based on the combined weight of the xylitol, glycerin, and thetotal polymer content.

In an aspect of the invention the film product contains citric acid andthe plasticizer is a xylitol, wherein 1) the amount of citric acid isabout equal to or less than the amount of xylitol by weight; and 2) thexylitol is present in an amount of about 10% to about 40% by weightbased on the combined weight of the xylitol and the total polymercontent.

In an aspect of the invention the film product contains citric acid andthe plasticizer is a combination of xylitol and glycerin, wherein thecombination of xylitol, glycerin, and citric acid is present in anamount of about 45% or less by weight based on the combined weight ofthe xylitol, glycerin, and the total polymer content.

In another embodiment of the present invention, there is provided a filmproduct including: i) about 60% sildenafil citrate; ii) about 18%pullulan; iii) about 0.1 polyethylene oxide; iv) about 5.3% xylitol; v)about 1.5% glycerin; and vi) about 4.7% citric acid; all percentages byweight based on the dry weight of the film product. This embodiment ofthe invention may further include: at least one sweetener, at least onecolorant, at least one emulsifier, and at least one flavor. In thisembodiment of the invention, the at least one sweetener is a combinationof fructose, sucralose, and maltodextrin; the at least one colorant is acombination of titanium dioxide and FD&C Blue #2; the at least oneemulsifier is glyceryl monooleate; and the at least one flavor is mint.

In a further embodiment of the present invention, there is provided afilm product including: a. at least one linear polysaccharide; b. atherapeutically effective amount of at least one active component; andc. at least one plasticizer.

As discussed below in the Examples, the Applicants have created a testfor estimating the time needed for the film to break when exposed towater. This has been named the Partial Immersion Dissolution (PID) test.Briefly, a film is partially immersed in water and the time fromimmersion to dissolution is recorded.

In an aspect of the invention the film product has a PID time of about60 seconds or less, or of about 30 seconds or less, or about 10 secondsor less. In other aspects of the invention the film product has a PIDtime of about 1 to about 60 seconds, or from about 2 to about 30, orabout 2 to about 10 seconds, or about 10 to about 30 seconds.

As discussed below in the Examples, the film products may be tested fortensile strength to determine the force required to break the film whensubjected to stress. In an aspect of the invention the film product hasa tensile strength of about 0.8 Newton/square millimeter or greater, forexample 1.0 N/mm² or greater.

Optional Components

A variety of other components and fillers may also be added to the filmsof the present invention. These may include, without limitation,surfactants; other anti-foaming agents; such as simethicone, whichpromote a smoother film surface by releasing oxygen from the film;thermo-setting gels such as pectin, carageenan, and gelatin, which helpin maintaining the dispersion of components; inclusion compounds, suchas cyclodextrins and caged molecules, which improve the solubilityand/or stability of certain active components; and crystal growthinhibitors, such as hydroxypropylmethylcellulose acetate succinate(“HPMCA”) and hydroxypropyl-β-cyclodextrin (“HPCD”), which inhibit thegrowth of crystals when coupled with appropriate linear polysaccharidesof the invention.

The variety of additives that can be incorporated into the inventivecompositions may provide a variety of different functions. Examples ofclasses of additives include excipients, lubricants, buffering agents,stabilizers, blowing agents, pigments, coloring agents, fillers, bulkingagents, sweetening agents, flavoring agents, fragrances, releasemodifiers, adjuvants, flow accelerators, mold release agents,granulating agents, diluents, binders, buffers, absorbents, glidants,adhesives, anti-adherents, acidulants, softeners, resins, demulcents,solvents, surfactants, emulsifiers; such as glycerol mono oleate,elastomers and mixtures thereof. These additives may be added with theactive ingredient(s).

Useful additives include, for example, gelatin, vegetable proteins suchas sunflower protein, soybean proteins, cotton seed proteins, peanutproteins, grape seed proteins, whey proteins, whey protein isolates,blood proteins, egg proteins, acrylated proteins, water-solublepolysaccharides such as alginates, carrageenans, guar gum, agar-agar,xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gumkaraya, gum tragancanth), pectin, water-soluble derivatives ofcellulose: alkylcelluloses, hydroxyalkylcelluloses, andhydroxyalkylalkylcelluloses, such as methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose,hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcelluloseesters such as cellulose acetate phthalate (CAP),hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses,carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such ascarboxymethylcellulose and their alkali metal salts; also suitable arephthalated gelatin, gelatin succinate, crosslinked gelatin, shellac,water soluble chemical derivatives of starch, cationically modifiedacrylates and methacrylates possessing, for example, a tertiary orquaternary amino group, such as the diethylaminoethyl group, which maybe quaternized if desired; and other similar polymers.

Such extenders may optionally be added in any desired amount desirablywithin the range of up to about 80%, desirably about 3% to 50% and moredesirably within the range of 3% to 20% based on the weight of allcomponents.

Further additives may be inorganic fillers, such as the oxides ofmagnesium aluminum, silicon, titanium, etc. desirably in a concentrationrange of about 0.02% to about 3% by weight and desirably about 0.02% toabout 1% based on the weight of all components.

There may further be added compounds to improve the flow properties ofthe starch material. Such compounds include animal or vegetable fats,desirably in their hydrogenated form, especially those which are solidat room temperature. These fats desirably have a melting point of 50° C.or higher. Preferred are tri-glycerides with C₁₂-, C₁₄-, C₁₆-, C₁₈-,C₂₀- and C₂₂-fatty acids. These fats can be added alone without addingextenders or plasticizers and can be advantageously added alone ortogether with mono- and/or di-glycerides or phosphatides, especiallylecithin. The mono- and di-glycerides are desirably derived from thetypes of fats described above, i.e. with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀-and C₂₂-fatty acids.

The total amounts used of the fats, mono-, di-glycerides and/orlecithins are up to about 5% and preferably within the range of about0.5% to about 2% by weight of the total composition

It is further useful to add silicon dioxide, calcium silicate, ortitanium dioxide in a concentration of about 0.02% to about 1% by weightof the total composition. These compounds act as texturizing agents.

These additives are to be used in amounts sufficient to achieve theirintended purpose. Generally, the combination of certain of theseadditives will alter the overall release profile of the activeingredient and can be used to modify, i.e. impede or accelerate therelease.

Lecithin is one surface active agent for use in the present invention.Lecithin can be included in the feedstock in an amount of from about0.25% to about 2.00% by weight. Other surface active agents, i.e.surfactants, include, but are not limited to, cetyl alcohol, sodiumlauryl sulfate, the Spans™ and Tweens™ which are commercially availablefrom ICI Americas, Inc. Ethoxylated oils, including ethoxylated castoroils, such as Cremophor® EL which is commercially available from BASF,are also useful. Carbowax™ is yet another modifier which is very usefulin the present invention. Tweens™ or combinations of surface activeagents may be used to achieve the desired hydrophilic-lipophilic balance(“HLB”). The present invention, however, does not require the use of asurfactant and films or film-forming compositions of the presentinvention may be essentially free of a surfactant while still providingthe desirable uniformity features of the present invention.

As additional modifiers which enhance the procedure and product of thepresent invention are identified, Applicants intend to include all suchadditional modifiers within the scope of the invention claimed herein.

Other ingredients include binders which contribute to the ease offormation and general quality of the films. Non-limiting examples ofbinders include starches, pregelatinize starches, gelatin,polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone, andpolyvinylalcohols.

Further potential additives include solubility enhancing agents, such assubstances that form inclusion compounds with active components. Suchagents may be useful in improving the properties of very insolubleand/or unstable actives. In general, these substances aredoughnut-shaped molecules with hydrophobic internal cavities andhydrophilic exteriors. Insoluble and/or unstable actives may fit withinthe hydrophobic cavity, thereby producing an inclusion complex, which issoluble in water. Accordingly, the formation of the inclusion complexpermits very insoluble and/or unstable actives to be dissolved in water.A particularly desirable example of such agents are cyclodextrins, whichare cyclic carbohydrates derived from starch. Other similar substances,however, are considered well within the scope of the present invention.

Forming the Film

The films of the present invention must be formed into a sheet prior todrying. After the desired components are combined to form amulti-component matrix, including the polymer, water, and an active, andother components as desired, the combination is formed into a sheet orfilm, by any method known in the art such as extrusion, coating,spreading, casting or drawing the multi-component matrix. If amulti-layered film is desired, this may be accomplished by co-extrudingmore than one combination of components which may be of the same ordifferent composition. A multi-layered film may also be achieved bycoating, spreading, or casting a combination onto an already formed filmlayer.

Although a variety of different film-forming techniques may be used, itis desirable to select a method that will provide a flexible film, suchas reverse roll coating. The flexibility of the film allows for thesheets of film to be rolled and transported for storage or prior tobeing cut into individual dosage forms. Desirably, the films will alsobe self-supporting or in other words able to maintain their integrityand structure in the absence of a separate support. Furthermore, thefilms of the present invention may use selected materials that areedible or ingestible.

Coating or casting methods are particularly useful for the purpose offorming the films of the present invention. Specific examples includereverse roll coating, forward roll coating, gravure coating, immersionor dip coating, metering rod or Mayer bar coating, slot die or extrusioncoating, gap or knife over roll coating, air knife coating, curtaincoating, or combinations thereof, especially when a multi-layered filmis desired.

Roll coating, or more specifically reverse roll coating, is particularlydesired when forming films in accordance with the present invention.This procedure provides excellent control and uniformity of theresulting films, which is desired in the present invention. In thisprocedure, the coating material is measured onto the applicator rollerby the precision setting of the gap between the upper metering rollerand the application roller below it. The coating is transferred from theapplication roller to the substrate as it passes around the supportroller adjacent to the application roller. Both three roll and four rollprocesses are common.

The gravure coating process relies on an engraved roller running in acoating bath, which fills the engraved dots or lines of the roller withthe coating material. The excess coating on the roller is wiped off by adoctor blade and the coating is then deposited onto the substrate as itpasses between the engraved roller and a pressure roller.

Offset Gravure is common, where the coating is deposited on anintermediate roller before transfer to the substrate.

In the simple process of immersion or dip coating, the substrate isdipped into a bath of the coating, which is normally of a low viscosityto enable the coating to run back into the bath as the substrateemerges.

In the metering rod coating process, an excess of the coating isdeposited onto the substrate as it passes over the bath roller. Thewire-wound metering rod, sometimes known as a Meyer Bar, allows thedesired quantity of the coating to remain on the substrate. The quantityis determined by the diameter of the wire used on the rod.

In the slot die process, the coating is squeezed out by gravity or underpressure through a slot and onto the substrate. If the coatingapproaches or is 100% solids, the process is termed “Extrusion” and inthis case, the line speed is frequently much faster than the speed ofthe extrusion. This enables coatings to be considerably thinner than thewidth of the slot.

The gap or knife over roll process relies on a coating being applied tothe substrate which then passes through a “gap” between a “knife” and asupport roller. As the coating and substrate pass through, the excess iscirculated back into the reservoir.

Air knife coating is where the coating is applied to the substrate andthe excess is “blown off” by a powerful jet from the air knife. Thisprocedure is useful for aqueous coatings.

In the curtain coating process, a bath with a slot in the base allows acontinuous curtain of the coating to fall into the gap between twoconveyors. The object to be coated is passed along the conveyor at acontrolled speed and so receives the coating on its upper face.

The present invention yields exceptionally uniform film products whenattention is paid to reducing the aggregation of the compositionalcomponents. By avoiding the introduction of and eliminating excessiveair in the mixing process, by selecting polymers and solvents to providea controllable viscosity, and by drying the film in a rapid manner fromthe bottom up, such films result.

The products and processes of the present invention rely on theinteraction among various steps of the production of the films in orderto provide films that substantially reduce the self-aggregation of thecomponents within the films. Specifically, these steps include theparticular method used to form the film, making the composition mixtureto prevent air bubble inclusions, controlling the viscosity of the filmforming composition, and the method of drying the film. Moreparticularly, a greater viscosity of components in the mixture isparticularly useful when the active is not soluble in the selected polarsolvent in order to prevent the active from settling out. However, theviscosity must not be too great as to hinder or prevent the chosenmethod of casting, which desirably includes reverse roll coating due toits ability to provide a film of substantially consistent thickness.

In addition to the viscosity of the film or film-forming components ormatrix, there are other considerations taken into account by the presentinvention for achieving desirable film uniformity. For example, stablesuspensions are achieved which prevent solid (such as drug particles)sedimentation in non-colloidal applications. One approach provided bythe present invention is to balance the density of the particulate(ρ_(p)) and the liquid phase (ρ₁) and increase the viscosity of theliquid phase (μ). For an isolated particle, Stokes law relates theterminal settling velocity (Vo) of a rigid spherical body of radius (r)in a viscous fluid, as follows:

V _(o)=(²gr^(r))(ρ_(p)−ρ₁)/9μ

At high particle concentrations, however, the local particleconcentration will affect the local viscosity and density. The viscosityof the suspension is a strong function of solids volume fraction, andparticle-particle and particle-liquid interactions will further hindersettling velocity.

Stokian analysis has shown that the incorporation of a third phase,dispersed air or nitrogen, for example, promotes suspension stability.Further, increasing the number of particles leads to a hindered settlingeffect based on the solids volume fraction. In dilute particlesuspensions, the rate of sedimentation, v, can be expressed as

v/V _(o)=1/(1+κφ)

where κ=a constant, and φ is the volume fraction of the dispersed phase.More particles suspended in the liquid phase results in decreasedvelocity. Particle geometry is also an important factor since theparticle dimensions will affect particle-particle flow interactions.

Similarly, the viscosity of the suspension is dependent on the volumefraction of dispersed solids. For dilute suspensions of non-interactionspherical particles, an expression for the suspension viscosity can beexpressed as:

μ/μ_(o)=1+2.5φ

where μ_(o) is the viscosity of the continuous phase and φ is the solidsvolume fraction. At higher volume fractions, the viscosity of thedispersion can be expressed as

μ/μ_(o)=1+2.5φ+C ₁φ² +C ₂φ³+

where C is a constant.

The viscosity of the liquid phase is critical and is desirably modifiedby customizing the liquid composition to a viscoelastic non-Newtonianfluid with low yield stress values. This is the equivalent of producinga high viscosity continuous phase at rest. Formation of a viscoelasticor a highly structured fluid phase provides additional resistive forcesto particle sedimentation. Further, flocculation or aggregation can becontrolled minimizing particle-particle interactions. The net effectwould be the preservation of a homogeneous dispersed phase.

The addition of hydrocolloids to the aqueous phase of the suspensionincreases viscosity, may produce viscoelasticity, and can impartstability depending on the type of hydrocolloid, its concentration andthe particle composition, geometry, size, and volume fraction. Theparticle size distribution of the dispersed phase needs to be controlledby selecting the smallest realistic particle size in the high viscositymedium, i.e., <500 μm. The presence of a slight yield stress or elasticbody at low shear rates may also induce permanent stability regardlessof the apparent viscosity. The critical particle diameter can becalculated from the yield stress values. In the case of isolatedspherical particles, the maximum shear stress developed in settlingthrough a medium of given viscosity can be given as

τ_(max)=3 Vμ/2r

For pseudoplastic fluids, the viscosity in this shear stress regime maywell be the zero shear rate viscosity at the Newtonian plateau.

A stable suspension is an important characteristic for the manufactureof a pre-mix composition which is to be fed into the film castingmachinery film, as well as the maintenance of this stability in the wetfilm stage until sufficient drying has occurred to lock-in the particlesand matrix into a sufficiently solid form such that uniformity ismaintained. For viscoelastic fluid systems, a rheology that yieldsstable suspensions for extended time period, such as 24 hours, must bebalanced with the requirements of high-speed film casting operations. Adesirable property for the films is shear thinning or pseudoplasticity,whereby the viscosity decreases with increasing shear rate. Timedependent shear effects such as thixotropy are also advantageous.Structural recovery and shear thinning behavior are importantproperties, as is the ability for the film to self-level as it isformed.

The rheology requirements for the inventive compositions and films arequite severe. This is due to the need to produce a stable suspension ofparticles, for example 30-60 wt %, in a viscoelastic fluid matrix withacceptable viscosity values throughout a broad shear rate range. Duringmixing, pumping, and film casting, shear rates in the range of 10-10⁵sec.⁻¹ may be experienced and pseudoplasticity is the preferredembodiment.

In film casting or coating, rheology is also a defining factor withrespect to the ability to form films with the desired uniformity. Shearviscosity, extensional viscosity, viscoelasticity, and structuralrecovery will influence the quality of the film. As an illustrativeexample, the leveling of shear-thinning pseudoplastic fluids has beenderived as

α^((n−1/n))=α_(o) ^((n−1/n))−((n−1)/(2n−1))(τ/K)^(1/n)(2π/λ)^((3+n)/n) h^((2n+1)/n) t

where α is the surface wave amplitude, α_(o) is the initial amplitude, λis the wavelength of the surface roughness, and both “n” and “K” areviscosity power law indices. In this example, leveling behavior isrelated to viscosity, increasing as n decreases, and decreasing withincreasing K.

Desirably, the films or film-forming compositions of the presentinvention have a very rapid structural recovery, i.e. as the film isformed during processing, it doesn't fall apart or become discontinuousin its structure and compositional uniformity. Such very rapidstructural recovery retards particle settling and sedimentation.Moreover, the films or film-forming compositions of the presentinvention are desirably shear-thinning pseudoplastic fluids. Such fluidswith consideration of properties, such as viscosity and elasticity,promote thin film formation and uniformity.

Thus, uniformity in the mixture of components depends upon numerousvariables. As described herein, viscosity of the components, the mixingtechniques and the rheological properties of the resultant mixedcomposition and wet casted film are important aspects of the presentinvention. Additionally, control of particle size and particle shape isa further consideration. Desirably, the size of the particulate aparticle size of 150 microns or less, for example 100 microns or less.Moreover, such particles may be spherical, substantially spherical, ornon-spherical, such as irregularly shaped particles or ellipsoidallyshaped particles. Ellipsoidally shaped particles or ellipsoids aredesirable because of their ability to maintain uniformity in the filmforming matrix as they tend to settle to a lesser degree as compared tospherical particles.

A number of techniques may be employed in the mixing stage to preventbubble inclusions in the final film. To provide a composition mixturewith substantially no air bubble formation in the final product,anti-foaming or surface-tension reducing agents are employed.Additionally, the speed of the mixing is desirably controlled to preventcavitation of the mixture in a manner which pulls air into the mix.Finally, air bubble reduction can further be achieved by allowing themix to stand for a sufficient time for bubbles to escape prior to dryingthe film. Desirably, the inventive process first forms a masterbatch offilm-forming components without active ingredients such as drugparticles or volatile materials such as flavor oils. The actives areadded to smaller mixes of the masterbatch just prior to casting. Thus,the masterbatch pre-mix can be allowed to stand for a longer timewithout concern for instability in drug or other ingredients.

In embodiments, the multi-component matrix is a polymer matrix, which isthen formed into a sheet as described above. In an embodiment, thepolymer matrix is a Non-Newtonian visco-elastic polymer matrix. In oneembodiment, the polymer matrix is a shear-thinning pseudoplastic fluidwhen exposed to shear rates of 10-10⁵ sec⁻¹.

Drying the Film

The drying step is also a contributing factor with regard to maintainingthe uniformity of the film composition. A controlled drying process isparticularly important when, in the absence of a viscosity increasingcomposition or a composition in which the viscosity is controlled, forexample by the selection of the polymer, the components within the filmmay have an increased tendency to aggregate or conglomerate. Analternative method of forming a film with an accurate dosage, that wouldnot necessitate the controlled drying process, would be to cast thefilms on a predetermined well. With this method, although the componentsmay aggregate, this will not result in the migration of the active to anadjacent dosage form, since each well may define the dosage unit per se.

When a controlled or rapid drying process is desired, this may beachieved through a variety of methods. A variety of methods may be usedincluding those that require the application of heat. The liquidcarriers are removed from the film in a manner such that the uniformity,or more specifically, the non-self-aggregating uniform heterogeneity,that is obtained in the wet film is maintained.

Desirably, the film is dried from the bottom of the film to the top ofthe film. Desirably, substantially no air flow is present across the topof the film during its initial setting period, during which a solid,visco-elastic structure is formed. The initial setting period, duringwhich a solid, visco-elastic structure is formed, can take place withinthe first few minutes, e.g. within about the first 4 minutes or aboutthe first 0.5 to about 4.0 minutes of the drying process.

In embodiments, at least portion of the solvent is rapidly removed fromthe matrix to form a visco-elastic film having the active substantiallyuniformly distributed throughout by rapidly increasing the viscosity ofthe matrix upon initiation of drying within about 4 minutes to maintainthe uniform distribution of the active by locking-in or substantiallypreventing migration of the active.

Controlling the drying in this manner prevents the destruction andreformation of the film's top surface, which results from conventionaldrying methods. This is accomplished by placing the liquid visco-elasticcomposition on the top side of a surface having top and bottom sides.Then, heat is initially applied to the bottom side of the visco-elasticfilm to provide the necessary energy to evaporate or otherwise removethe liquid carrier. The films dried in this manner dry more quickly andevenly as compared to air-dried films, or those dried by conventionaldrying means. In contrast to an air-dried film that dries first at thetop and edges, the films dried by applying heat to the bottom drysimultaneously at the center as well as at the edges. This also preventssettling of ingredients that occurs with films dried by conventionalmeans.

In embodiments of the present invention, any top air flow does notovercome the inherent viscosity of the polymer matrix (e.g., thevisco-elastic film) and/or any top air flow is insufficient to cause oneor more of the following: (i) surface skinning prior to drying the depthof the film, (ii) surface rippling; (iii) self-aggregation ofcomponents; (iv) non-uniformity in the thickness of the film, and (v)non-uniformity of mass per unit volume.

The endogenous or internal temperature of the films should be less thanabout 100° C., desirably about 90° C. or less, and most desirably about80° C. or less within the initial setting period (e.g., within about thefirst 4 minutes of the drying of the film). The temperature inside thedrying apparatus (i.e., exogenous to the film) may be any desiredtemperature and may be well above or below 100° C. In embodiment of thepresent invention, the differential in temperature between theendogenous or internal temperature and the temperature inside the dryingapparatus is at least about 5° C., preferably from about 5° C. to about30° C.

Another method of controlling the drying process, which may be usedalone or in combination with other controlled methods as disclosed aboveincludes controlling and modifying the humidity within the dryingapparatus where the film is being dried. In this manner, the prematuredrying of the top surface of the film is avoided.

Additionally, it has also been discovered that the length of drying timecan be properly controlled, i.e. balanced with the heat sensitivity andvolatility of the components, and particularly the flavor oils anddrugs. The amount of energy, temperature and length and speed of theconveyor can be balanced to accommodate such actives and to minimizeloss, degradation or ineffectiveness in the final film.

A specific example of an appropriate drying method is that disclosed byMagoon. Magoon is specifically directed toward a method of drying fruitpulp. However, the present inventors have adapted this process towardthe preparation of thin films.

The method and apparatus of Magoon are based on an interesting propertyof water. Although water transmits energy by conduction and convectionboth within and to its surroundings, water only radiates energy withinand to water. Therefore, the apparatus of Magoon includes a surface ontowhich the fruit pulp is placed that is transparent to infraredradiation. The underside of the surface is in contact with a temperaturecontrolled water bath. The water bath temperature is desirablycontrolled at a temperature slightly below the boiling temperature ofwater. When the wet fruit pulp is placed on the surface of theapparatus, this creates a “refractance window.” This means that infraredenergy is permitted to radiate through the surface only to the area onthe surface occupied by the fruit pulp, and only until the fruit pulp isdry. The apparatus of Magoon provides the films of the present inventionwith an efficient drying time reducing the instance of aggregation ofthe components of the film.

Another method of controlling the drying process involves a zone dryingprocedure. A zone drying apparatus may include a continuous belt dryingtunnel having one or more drying zones located within. The conditions ofeach drying zone may vary, for example, temperature and humidity may beselectively chosen. It may be desirable to sequentially order the zonesto provide a stepped up drying effect.

In aspects of the invention, the speed of the zone drying conveyordesirably is constant. Alternatively, the speed may be altered at aparticular stage of the drying procedure to increase or decreaseexposure of the film to the conditions of the desired zone. Whethercontinuous or modified, the zone drying dries the film without surfaceskinning

To further control temperature and humidity, the drying zones mayinclude additional atmospheric conditions, such as inert gases. The zonedrying apparatus further may be adapted to include additional processesduring the zone drying procedure, such as, for example, spraying andlaminating processes, so long as controlled drying is maintained inaccordance with the invention.

The films may initially have a thickness of about 500 μm to about 1,500μm, or about 20 mils to about 60 mils, and when dried have a thicknessfrom about 3 μm to about 500 μm, or about 0.1 mils to about 20 mils.Desirably, the dried films will have a thickness of about 1 mils toabout 10 mils, more desirably about 2 mils to about 8 mils, and evenmore desirably, from about 3 mils to about 6 mils.

Testing Films for Uniformity

It may be desirable to test the films of the present invention forchemical and physical uniformity during the film manufacturing process.In particular, samples of the film may be removed and analyticallytested for uniformity in film components between various samples. Filmthickness and overall appearance may also be checked for physicaluniformity. Active uniform films are desired, particularly for filmscontaining pharmaceutical active components due to safety and efficacyreasons.

A method for testing uniformity in accordance with the present inventionincludes sampling while conveying a film through a manufacturingprocess. This process may include subjecting the film to dryingprocesses, dividing the film into individual dosage units, and/orpackaging the dosages, among others. As the film is conveyed through themanufacturing process, for example on a conveyor belt apparatus, it iscut widthwise into at least one portion. The at least one portion hasopposing ends that are separate from any other film portion. Forinstance, if the film is a roll, it may be cut into separate sub-rolls.Cutting the film may be accomplished by a variety of methods, such aswith a knife, razor, laser, or any other suitable means for cutting afilm.

The cut film then may be sampled by removing small pieces from each ofthe opposed ends of the portion(s), without disrupting the middle of theportion(s). Leaving the middle section intact permits the predominantportion of the film to proceed through the manufacturing process withoutinterrupting the conformity of the film and creating sample-inductedgaps in the film. Accordingly, the concern of missing doses isalleviated as the film is further processed, e.g., packaged. Moreover,maintaining the completeness of cut portions or sub-rolls throughout theprocess will help to alleviate the possibility of interruptions infurther film processing or packaging due to quality control issues, forexample, alarm stoppage due to notice of missing pieces.

After the end pieces, or sampling sections, are removed from the filmportion(s), they may be tested for physical defects in the film and fordesired amount of active uniformity in the content of components betweensamples. Any conventional means for examining and testing the filmpieces may be employed, such as, for example, visual inspection, use ofanalytical equipment, and any other suitable means known to thoseskilled in the art. Testing for content uniformity of the desired amountof active may be carried out by one or more analytic methods includinghigh pressure liquid chromatography (HPLC) or near-infrared (NIR)spectroscopy. If the testing results show non-uniformity between filmsamples, the manufacturing process may be altered. For example, thecompositional components, compositional rheology, drying conditions, andmixing conditions may be changed. Altering the drying conditions mayinvolve changing the temperature, drying time, film speed through theoven, and dryer positioning, among others.

Moreover, it may be desirable to repeat the steps of sampling andtesting throughout the manufacturing process. Testing at multipleintervals may ensure that physically uniform film dosages and filmdosages with desired active content uniformity are continuouslyproduced. Alterations to the process can be implemented at any stage tominimize non-uniformity between samples.

In embodiments, the films of the present invention have a substantiallyuniform content of active by weight per unit volume of the film. In anembodiment, the amount of active in substantially equally sizedindividual dosage units of the film varies by no more than 10% by weightfrom a desired amount (e.g., the label claim amount, the dosage amount,etc.). In another embodiment, the amount of active in substantiallyequally sized individual dosage units of the film varies by no more than10% between units.

However, it is to be noted that visual inspection and/or comparison orevaluation of the weight of samples of the film product or individualdosage units of the film product alone are not sufficient to demonstrateuniformity of content of the active in the film or individual dosageunits of the film product.

As used herein, the term desired amount (e.g., the label claim amount orthe dosage amount) of active component per dosage unit means an amountof active component that is intended to be in each dosage unit. In thecase of certain products, e.g., pharmaceutical products, there may be anamount of active component claimed on the label of the product. Thus, adesired active component (or drug) label claim per dosage unit means theamount of active component that is claimed to be in each dosage unitbased upon the label of the product.

Uniformity of content of active component in a lot may be determinedthrough establishing the amount of active component (A_(N(i))) actuallypresent in each sampled individual dosage unit from the same lot (N) asdetermined by taking the difference between the amount of activecomponent in the sample with the most amount of active component(Max_(LOT(N))) minus the amount of active component in the sample withthe least amount of active component (Min_(LOT(N))) and dividing thedifference by the average amount of active component in the lot samples(Lot_((N)) Sample Average).

(Max_(LOT(N))−Min_(LOT(N)))/((A _(N(1)) +A _(N(2)) +++A _(N(10)))/10).

Uniformity of content across different lots may be determined throughestablishing the amount of active component actually present in each ofthe sampled individual dosage unit from the different lots and comparingthat amount of active component with a desired amount of activecomponent contained therein. The desired amount of active component,when it is a pharmaceutical, may be referred to as the “label claimamount”, thus identifying the amount of pharmaceutical active in thefilm dosage unit.

In an embodiment, the amount of active in substantially equally sizedindividual dosage units of the film is not less than 75% or greater than125% of the desired amount, preferably not less than 85% or greater than115% of the desired amount.

Using the methods of the present invention, the uniformity of contentwith respect to desired amount of active is achievable both withinindividual lots of the film and between different lots of film duringlarge-scale manufacturing of the film. Using the methods of the presentinvention, this uniformity of content with respect to the amount ofactive in substantially equally sized individual dosage units isachievable both within individual lots of the film and between differentlots of film during large-scale manufacturing of the film.

Uses of Films

The films of the present invention are well suited for many uses. Thehigh degree of desired active uniformity in the film makes themparticularly well suited for incorporating pharmaceuticals. Furthermore,the polymers used in construction of the films may be chosen to allowfor a range of disintegration times for the films. A variation orextension in the time over which a film will disintegrate may achievecontrol over the rate that the active is released, which may allow for asustained release delivery system. In addition, the films may be usedfor the administration of a desired amount of an active to any ofseveral body surfaces, especially those including mucosal surfaces, suchas those found in the oral (i.e., sublingual, lingual, buccal, andgingival), anal, vaginal, ocular, nasal, aural, ophthalmological, andperitoneal environments; the surface of a wound, either on a skinsurface or within the body such as during surgery or left in place aftersurgery to deliver the desired amount of active after the surgicalprocedure is completed; the surface of an organ (i.e., kidney, lung,liver, heart, etc.), and other similar surfaces.

The films may be used to orally administer an active. This isaccomplished by preparing the films as described above and introducingthem to the oral cavity of an animal, such as a mammal. This film may beprepared and adhered to a second or support layer from which it isremoved prior to use, i.e. introduction to the oral cavity. An adhesivemay be used to attach the film to the support or backing material whichmay be any of those known in the art, and is preferably not watersoluble. If an adhesive is used, it will desirably be a food gradeadhesive that is ingestible and does not alter the properties of theactive. Mucoadhesive compositions are particularly useful. The filmcompositions in many cases serve as mucoadhesives themselves.

The films may be applied under or to the tongue of the mammal. When thisis desired, a specific film shape, corresponding to the shape of thetongue may be preferred. Therefore the film may be cut to a shape wherethe side of the film corresponding to the back of the tongue will belonger than the side corresponding to the front of the tongue.Specifically, the desired shape may be that of a triangle or trapezoid.Desirably, the film will adhere to the oral cavity preventing it frombeing ejected from the oral cavity and permitting more of the active tobe introduced to the oral cavity as the film dissolves.

Another use for the films of the present invention takes advantage ofthe films' tendency to dissolve quickly when introduce to a liquid. Anactive may be introduced to a liquid by preparing a film in accordancewith the present invention, introducing it to a liquid, and allowing itto dissolve. This may be used either to prepare a liquid dosage form ofan active, or to flavor a beverage.

The films of the present invention are desirably packaged in sealed, airand moisture resistant packages to protect the active from exposureoxidation, hydrolysis, volatilization and interaction with theenvironment. Moreover, the films of the present invention dissolveinstantly upon contact with saliva or mucosal membrane areas,eliminating the need to wash the dose down with water.

Desirably, a series of such unit doses are packaged together inaccordance with the prescribed regimen or treatment, e.g., a 10-90 daysupply, depending on the particular therapy. The individual films can bepackaged on a backing and peeled off for use.

The features and advantages of the present invention are more fullyshown by the following examples which are provided for purposes ofillustration, and are not to be construed as limiting the invention inany way.

EXAMPLES

Applicants have developed or employed several subjective and objectivetests for evaluation of the robustness of a formulation for high speedproduction and storage life of the film product.

180 Degree Flex Test

In this test, a film strip is folded end-to-end (180 degrees) and judgedfor its pliability (softness and flexibility). If the film cracks, it isconsidered unacceptable as it may break during packaging on theautomated line. Pliability of the film is also an important element ofpatient satisfaction with the dose form because a soft, flexible filmstrip is easy to apply as compared to a hard, stiff film strip.

Dry Flex

In this test, to stress the film and duplicate the effects of long termstorage, all the water is evaporated from the film using a thermalgravimetric balance. The film is then immediately folded using the 180degree flex test. If the film breaks or cracks it fails.

Folding Endurance

In this test, folding endurance is determined by repeated folding of thestrip at the same place until the strip breaks. The number of times thefilm is folded without breaking is computed as the folding endurancevalue. A goal of surviving multiple folds (e.g., 180 degrees) withoutbreaking or failing is indicator of the tensile strength and flexibilityof the film which is important for taking the high speed route throughthe packaging machine that the film must endure.

Aged Brittleness

In this test, the film is exposed to room atmosphere, temperature, andhumidity, and folded (e.g., 180 degrees) each day to determine if andwhen the film becomes brittle. This test is a good indicator of longterm storage properties of the film.

Dryness Test/Tack Tests

About eight stages of film drying process have been identified and theyare set-to-touch, dust-free, tack-free (surface dry), dry-to-touch,dry-hard, dry-through (dry-to-handle), dry-to-recoat and dry print free.Although these tests are primarily used for paint films, most of thestudies can be adapted intricately to evaluate pharmaceutical OSF aswell. Tack is the tenacity with which the strip adheres to a surface orto its self after being pressed into contact. Two strips are pressedtogether between the thumb and forefinger using a gloved hand. If thestrips stick then they fail if the films come apart without stickingthen they pass.

Partial Immersion Dissolution (PID)

This test is used to estimate the time needed for the film to break whenexposed to water. This test is applicable to film strips and may beregarded as a surrogate for the disintegration test performed ontablets. In this test, an alligator clamp is attached to the top portionof the film and a weight of 2.8 grams is attached to the bottom portionof the film. The film is gently lowered into a water bath (37.0±0.2° C.)so that half of the film is in the water and the other half remainsoutside the water. A stopwatch is started at immersion and is stoppedwhen the submerged part of the film dissolves enough to separate fromthe top half of the film. Experience has shown that the target value forPID depends greatly on the specific application for which the filmformulation is designed. Film strips designed for rapid dissolution inthe oral cavity or on the oral mucosa generally require a PID value of 2to 10 seconds. Film strips designed for intermediate dissolution in theoral cavity or on the oral mucosa generally require a PID value of 10 to30 seconds. PID dissolution is used as a predictive tool for In Vivodissolution since active containing films cannot easily be tested invivo due to restrictions on human exposure to active pharmaceuticals.

Tensile Strength

In this test, the tensile strength of the film is measured to determinethe force required to break the film when subjected to stress. Testingis performed by mounting opposite ends of the film on clamps of aTexture Analyzer (Texture Technologies Corp. Mode TAXT, Scarsdale,N.Y.). The two clamps are 10-15 mm apart and programmed to separate at arate of 5 mm/sec to a distance of 20 mm with a trigger force of 5.0 g.The recorded data includes tensile strength, tensile force, and %elongation. Tensile strength is calculated by dividing the resultingforce required to break the film (N) by the cross-sectional are of thefilm (mm₂). These measurements are development tools for quantifying andcomparing the mechanical strength of various formulations. A tensilestrength of 0.8 N/mm² is considered the lower limit necessary fordownstream processing in the automated (commercial) packaging line.

Disintegration Test

In this test, films are evaluated for disintegration time by placingthem on the top surface of a beaker of water at 37° C. and evaluatingthe time taken for the film to break up and start to disperse. Noagitation is used in the test and this is a pure test of wetting anddiffusion.

Shock Sensitivity

In this test, a die of the correct size made by DieMasters (PacificMissouri) is used with compression to cut the sheet into individual doseform. The film edges are visually observed for irregularities aftercutting the strips into the final size. If the edges are clean (like acut piece of paper) then the film passes. If the edges are jagged andirregular then the film fails. This subjective test is an indicator offilms that will create production slowdowns during a high speedpackaging process.

Examples 1-22

Twenty two film formulations were prepared (Examples 1-22) and tested asshown below. These films included various plasticizers or combinationsof plasticizers as shown in Table 1. These plasticizers were Sorbitol,erythritol, glycerin, xylitol, citric acid, PEG, propylene glycol,dextrose, and maltitol. The below ingredients were added to a fabricatedglass bowl and mixed using a Degussa Dental Multivac Stirrer which wasequipped with a gate impeller. The ingredients were mixed to form acoating solution as follows:

1. Pullulan*

2. Plasticizer (Table 1)**

3. Antifoaming agent (0.065%)

4. Distilled Water (67.5%)

-   *Total % of Pullulan+Plasticizer=32.435%-   ** Plasticizers used were added as w/w % of dry polymer    weight+plasticizer

TABLE 1 Film Composition for Pullulan/Plasticizer Evaluation (numericalvalues for the plasticizers refer to the w/w % based on the polymer dryweight + plasticizer) Plasticizer Propylene Example Sorbitol ErythritolGlycerin Xylitol Citric Acid PEG Glycol Dextrose Maltitol 1 30 2 30 3 154 30 10 5 26.5 8.75 6 30 7 30 8 10 9 30 10 15 15 11 20 10 12 20 10 13 1010 10 14 22.5 15 30 16 30 17 30 18 10 19 40 20 10 21 40 22 18.75The ingredients were mixed under a vacuum to form a coating solutionaccording to the following schedule:

20 Minutes Stirring = 125 rpm Vacuum = 60% (18 in Hg) 20 MinutesStirring = 125 rpm Vacuum = 90% (26 in Hg) 20 Minutes Stirring = 125 rpmVacuum = 95% (27 in Hg) 12 Minutes Stirring = 125 rpm Vacuum = 98% (28in Hg)  8 Minutes Stirring = 125 rpm Vacuum = 100% (29 in Hg)

The coating solution was cast into wet film using the K-Control Coaterwith the micrometer adjustable wedge bar set at 500 microns onto Mylarsubstrate. The cast wet film was dried for 18 minutes in an 80° C.convection air oven. The dried film had 1.33% moisture content. Thepercent moisture was determined using a Mettler HR73 Moisture Analyzer.The film had a thickness of 3.5 to 4 mils.

The film was observed for flexibility out of the oven and out of themoisture analyzer after completely drying. The film was also observedsubjectively for strength by pulling on the film.

The film was allowed to stand overnight in room atmosphere. Afterstanding overnight, the film was cut into 18 mm×22 mm strips using asteel rule die fabricated by DieMasters. The strips were observed forshock sensitivity and tackiness. A 360 degree bend test was run on afilm strip to determine whether the film strips fails at less than 100bends. The Partial Immersion Dissolution (PID) was measured on a 45 to50 mg strip using 37° C. water.

Films that passed the initial testing were allowed to sit at roomtemperature and room atmospheric conditions and tested over time toobserve any brittleness with aging.

The results of the testing are shown in Table 2.

TABLE 2 Evaluation of Plasticizers on Pullulan Film Properties. FilmProperties Analysis Example Tack Initial Flex Dry Flex Strength InitialBrittleness Aged Brittleness Bend Test Shock Sensitive 1 Sticky P P GoodP F N/A F 2 Sticky P P Good P F N/A F 3 Not Stick F F Good F N/A N/A F 4Sticky P P Good P F N/A F 5 Sticky P P Good P F N/A F 6 Not Stick P PGood P P (22 days) P Slight 7 Not Stick F F N/A F F N/A F 8 Not Stick PF N/A P F N/A N/A 9 Sticky P P N/A P P P P 10 Not Stick P P Good P P P P11 Not Stick P P N/A P F F F 12 Sticky P P N/A P P P P 13 Not Stick P PN/A P P P P 14 Sticky P P Good P P P P 15 Not Stick F F N/A F N/A N/A F16 Not Stick F F N/A F N/A N/A F 17 Not Stick F F N/A F N/A N/A N/A 18Not Stick F F N/A F F N/A N/A 19 Sticky P P N/A P P (22 days) N/A N/A 20Not Stick F F N/A F F N/A N/A 21 Sticky P P N/A P F N/A N/A 22 Not StickP P Good P P P P

Comparative Examples 23-27

Comparative film compositions were prepared using the ingredients andprotocol shown below.

Ingredients:

1. 27.75 g (46.25%) HPMC

2. 13.875 g (23.125%) Polyethylene Oxide

3. 18.5 g of Maltitol Syrup

4. 1.8 g (3.000%) Artificial Sweetener

5. 2.4 g (4.000%) Flavoring Agent

6. 0.3 g (0.500%) Antifoaming Agent

7. 0.024 g Colorant

8. 135.375 g Distilled Water

Ingredients 1, 3, and 6 were mixed together with a spatula in afabricated glass bowl. Ingredients 7 and 8 were then added to the bowland mixed further with a spatula. A coating solution was prepared fromthis mixture as described below using the Degussa Dental MultivacCompact.

The mixture was stirred for 44 minutes at 125 rpm under a vacuum (100%(29 in Hg)). Distilled water was added to obtain QS. A blend ofingredients 2 and 4 was then added to the bowl. Stirring was continuedfor another 20 minutes at 125 rpm under a vacuum (60% (18.5 in Hg)).Stirring was continued for another 60 minutes at 125 rpm under a vacuum(100% (29 in Hg)). Distilled water was added to obtain QS. Stirring wascontinued for another 4 minutes at 125 rpm under a vacuum (100% (29 inHg)). The mixture was then allowed to stand for 80 minutes withoutstirring or vacuum. Distilled water was added to obtain QS. Ingredient 5was then added. The mixture was then stirred for 8 minutes at 125 rpmunder a vacuum (100% (29 in Hg)) to form the coating solution.

The coating solution was cast into wet film using the K-Control Coaterwith the micrometer adjustable wedge bar set at 200, 400, 600, 800, and1000 microns onto Mylar substrate. The wet films were dried for 18 to 30minutes depending on the micrometer wedge bar setting in an 80° C.convection air oven. The dried films had a % moisture content of 0.79%to 2.21% when tested using the Mettler HR73 Moisture Analyzer. The filmshad a thickness of 1.9 to 8 mils. The dried films were cut into 22 mm×20mm strips which had a weight range of 18 to 97 mg.

The dried film strips were tested for Partial Immersion Dissolution at37° C. and dispersion time after placing on top of 37° C. water in a 500ml beaker without stirring. The results are shown in Table 3.

TABLE 3 Dissolution Testing of HPMC/PEO/Maltitol Based Film* Strips (22mm × 20 mm) Dispersion Time Example Film Strip Weight in 37° C. WaterNo. Thickness (mg) PID 37° C. Without Stirring 23 1.9 mils 18 mg  1.4sec. 22.3 sec. 24 3.3 mils 36 mg  9.4 sec.   3 min 53 sec. 25 4.75 mils 56 to 57 mg 24.0 sec.   9.0 min. 26 6.15 mils  78 to 79 mg 46.0 sec 20.0 min 27 8.0 mils 95 to 97 mg 1 min. 8 sec. 20 min. 23 sec.

Examples 28-32

Film products of the invention were prepared using the ingredients andprotocol shown below.

Ingredients:

1. 33.67 g (64.75%) Pullulan

2. 7.215 g (13.875%) Xylitol

3. 7.215 g (13.875%) Glycerin

4. 1.56 g (3.000%) Artificial Sweetener

5. 2.08 g (4.000%) Flavoring Agent

6. 0.26 g (0.500%) Antifoaming Agent

7. 0.021 g Colorant

8. 108 g Distilled Water

Ingredients 1, 2, 3, 4, 6, 7, and 8 were added to a fabricated glassbowl. The coating solution was prepared as described below using theDegussa Dental Multivac Compact. The mixture was stirred for 20 minutesat 125 rpm under a vacuum (60% (18.5 in Hg)). The mixture was thenstirred for 20 minutes at 125 rpm under a vacuum (90% (26 in Hg)). Themixture was then stirred for 20 minutes at 125 rpm under a vacuum (95%(27 in Hg)). The mixture was then stirred for 12 minutes at 125 rpmunder a vacuum (98% (28 in Hg)). Distilled water to obtain QS.Ingredient 5 was added. The mixture was then stirred for 8 minutes at125 rpm under a vacuum (100% (29 in Hg)) to form a coating solution.

The coating solution was cast into wet film using the K-Control Coaterwith the micrometer adjustable wedge bar set at 200, 360, 560, 780, and950 microns onto Mylar substrate. The wet films were dried for 15 to 34minutes depending on the micrometer wedge bar setting in an 80° C.convection air oven. The dried films had % moisture of 1.44% to 2.80%when tested using the Mettler HR73 Moisture Analyzer. The dried filmshad a thickness of 1.35 to 6.3 mils. The dried films were cut into 22mm×20 mm strips which had a weight range of 18 to 97 mg. The dried filmstrips were tested for Partial Immersion Dissolution at 37° C. anddispersion time after placing on top of 37° C. water in a 500 ml beakerwithout stirring. The results are shown in Table 4.

TABLE 4 Dissolution Testing on Pullulan/Xylitol/Glycerin Based Film**Strips (22 × 20 mm) Dispersion Time Example Film Strip Weight in 37° C.Water No. Thickness (mg) PID 37° C. Without Stirring 28 1.35 mils  18 to19 mg  0.8 sec.  4.1 sec. 29 2.6 mils 35 to 37 mg 3.06 sec.  6.5 sec. 304.3 mils 56 to 58 mg  5.8 sec. 23.6 sec. 31 5.25 mils  77 to 79 mg 10.3sec. 33.0 sec. 32 6.3 mils 95 to 97 mg 15.2 sec. 3 min. 44.0 sec.

FIG. 1 shows a comparison of the partial immersion dissolution time forthe comparative film compositions (HPMC/PEO) and inventive film products(Pullulan). FIG. 2 shows the partial immersion dissolution time data forthe comparative film compositions and inventive film products andincludes an extrapolation of the partial immersion dissolution time forgreater weights of film. Based on the examples, the use of xylitol andglycerol, alone or combined, with or without citric acid, produces OSFthat pass all the subjective tests for high speed film production andpackaging and storage. Moreover, such films have the ability to loadhigher amounts of active pharmaceutical ingredient per film and stillallow dissolution at a faster PID time when compared to traditional OSFpolymer formulations. Four to five times more film weight may be loadedinto the same size film (area) and while still maintaining the PID timewhen compared to a traditional polymer film formulation. Moreover, thesedata demonstrate that there is a preferred range for these plasticizersin the film product.

Examples 33-38

Film products of the invention were prepared as described above with theingredients set forth in the tables below.

Example 33 Sildenafil Citrate 70 mg (50 mg Sildenafil Base Equivalent)

TABLE 5 Film product of the invention with 50 mg Sildenafil baseequivalent. Dry Basis Dry Basis Wet Basis Weight Composition (% w/w)(mg/film) (% w/w) Charged (g) Sildenafil Citrate 61.508 70.008 31.46326.086 Monosaccharide 0.545 0.620 0.279 0.231 Sweetener Pullulan 16.45418.728 8.417 6.979 Xylitol 5.328 6.064 2.725 2.259 Artificial Sweetener0.679 0.773 0.347 0.288 Starch Derivative 1.044 1.188 0.534 0.443Glycerin 1.565 1.781 0.800 0.663 Antifoaming Agent 1.565 1.781 0.8000.663 Opacifier 2.216 2.522 1.133 0.939 Polyether 0.283 0.322 0.1450.120 Citric Acid 4.715 5.367 2.412 2.000 Colorant 0.071 0.081 0.0360.030 Flavoring Agent 4.027 4.584 2.060 1.708 Sum 113.819 51.151 42.409Water Purified 4.101 48.849 40.499 Total 100.000 117.920 100.000 82.908

The film product of Example 33 had the physical data shown in Table 6(below).

TABLE 6 Physical data a film product of the invention with 50 mgSildenafil base equivalent (Example 33). Tensile Physical Data 50 mgExample Data* Storage conditions PID (sec) N/mm Initial analysis 6 1.46025° C./60% RH 2 weeks 6 NT 3 weeks NT 1.196 4 weeks 6 2.431 3 months 61.607 40° C./75% RH 1 week 7 1.139 2 weeks 6 NT 3 weeks NT 5.363 4 weeks6 2.657 3 months 5 2.062

Example 34 Sildenafil Citrate 140 mg (100 mg Sildenafil Base Equivalent)

TABLE 7 Film product of the invention with 100 mg Sildenafil baseequivalent. Dry Basis Dry Basis Wet Basis Weight Component (% w/w)(mg/film) (% w/w) Charged (g) Sildenafil Citrate 63.283 140.001 32.38426.846 Monosaccharide 0.542 1.199 0.277 0.230 Sweetener Pullulan 14.00030.972 7.164 5.939 Xylitol 5.327 11.785 2.726 2.260 Artificial Sweetener0.679 1.502 0.347 0.288 Starch Derivative 1.045 2.312 0.535 0.444Glycerin 1.565 3.462 0.801 0.664 Antifoaming Agent 1.565 3.462 0.8010.664 Opacifier 2.216 4.902 1.134 0.940 Polyether 1.000 2.212 0.5120.424 Citric Acid 4.691 10.378 2.401 1.990 Colorant 0.073 0.161 0.0370.031 Flavoring Agent 4.014 8.880 2.054 1.703 Sum 221.228 51.173 42.423Water Purified 7.962 48.827 40.478 Total 100.000 229.190 100.000 82.901

Example 35 Sildenafil Citrate 140 mg (100 mg Sildenafil Base Equivalent)

TABLE 8 Film product of the invention with 100 mg Sildenafil baseequivalent. Dry Basis Dry Basis Wet Basis Weight Component (% w/w)(mg/film) (% w/w) Charged (g) Sildenafil Citrate 60.183 140.004 30.78925.524 Monosaccharide 0.542 1.261 0.277 0.230 Sweetener Pullulan 18.00041.873 9.209 7.634 Xylitol 5.328 12.395 2.726 2.260 Artificial Sweetener0.679 1.580 0.347 0.288 Starch Derivative 1.044 2.429 0.534 0.443Glycerin 1.565 3.641 0.801 0.664 Antifoaming Agent 1.565 3.641 0.8010.664 Opacifier 2.216 5.155 1.134 0.940 Polyether 0.100 0.233 0.0510.042 Citric Acid 4.691 10.913 2.400 1.990 Colorant 0.073 0.170 0.0370.031 Flavoring Agent 4.014 9.338 2.054 1.702 Sum 232.633 51.160 42.412Water Purified 8.367 48.840 40.488 Total 100.000 241.000 100.000 82.900

Example 36 Sildenafil Citrate 140 mg (100 mg Sildenafil Base Equivalent)

TABLE 9 Film product of the invention with 100 mg Sildenafil baseequivalent. Dry Basis Dry Basis Wet Basis Weight Component (% w/w)(mg/film) (% w/w) Charged (g) Sildenafil Citrate 64.184 140.004 32.86727.247 Monosaccharide 0.542 1.182 0.277 0.230 Sweetener Pullulan 14.00030.538 7.169 5.943 Xylitol 5.327 11.620 2.728 2.262 Artificial Sweetener0.679 1.481 0.348 0.288 Starch Derivative 1.044 2.277 0.535 0.444Glycerin 1.565 3.414 0.801 0.664 Antifoaming agent 1.565 3.414 0.8010.664 Opacifier 2.216 4.834 1.135 0.941 Polyether 0.100 0.218 0.0510.042 Citric Acid 4.691 10.232 2.402 1.991 Colorant 0.073 0.159 0.0370.031 Flavoring Agent 4.014 8.756 2.056 1.704 Sum 218.129 51.207 42.451Water Purified 7.851 48.793 40.449 Total 100.000 225.980 100.000 82.900

Example 37 Sildenafil Citrate 140 mg (100 mg Sildenafil Base Equivalent)

TABLE 10 Film product of the invention with 100 mg Sildenafil baseequivalent. Dry Basis Dry Basis Wet Basis Weight Composition (% w/w)(mg/film) (% w/w) Charged (g) Sildenafil Citrate 59.284 140.005 30.33725.149 Monosaccharide 0.542 1.280 0.277 0.230 Sweetener Pullulan 18.00042.509 9.211 7.636 Xylitol 5.327 12.580 2.726 2.260 Artificial Sweetener0.679 1.604 0.348 0.288 Starch Derivative 1.044 2.466 0.534 0.443Glycerin 1.565 3.696 0.801 0.664 Antifoaming Agent 1.565 3.696 0.8010.664 Opacifier 2.216 5.233 1.134 0.940 Polyether 1.000 2.362 0.5120.424 Citric Acid 4.691 11.078 2.400 1.990 Colorant 0.073 0.172 0.0370.031 Flavoring Agent 4.014 9.479 2.054 1.703 Sum 236.160 51.172 42.422Water Purified 8.500 48.828 40.478 Total 100.000 244.660 100.000 82.900

Example 38 Loratadine 100 mg

TABLE 11 Film product of the invention with 100 mg loratadine. Dry BasisDry Basis Ingredient (% w/w) (mg/film) Pullulan 27.94* 46.58 Xylitol5.99* 9.98 Glycerin 5.99* 9.98 Antifoaming Agent 0.08 0.13 Loratadine60.00 100.00 Total 100 166.67

Comparative Example 39

Loratadine 100 mg in HPMC/PEO Formulation

TABLE 12 Comparative film with 100 mg loratadine. Dry Basis Dry BasisIngredient (% w/w) (mg/film) HPMC 19.96 33.28 Maltitol 9.98 16.63 PEO9.98 16.63 Antifoaming Agent 0.08 0.13 Loratadine 60.00 100.00 Total 100166.67

Examples 38 and 39 were the same size and weight −22 mm×20 mm and 166.67mg.

Table 13 below shows the percent of plasticizer, polymer, and acid forExamples 33-38 and provides the weight ratio of the combination of theplasticizer and acid to the combined weight of the plasticizer, acid,and polymer.

TABLE 13 Plasticizer, Acid, Polymer comparison. Total Plasticizer andAcid Polymer Plasticizer Wt. % Citric Plasticizer W/W % of Polymer +Example Wt. % Xylitol Glycerin Acid Wt. % Acid + Plasticizer 33 17.55.33 1.57 4.72 11.62 39.9 34 16 5.33 1.57 4.69 11.59 42 35 19.1 5.331.57 4.69 11.59 37.8 36 15.1 5.33 1.57 4.69 11.59 43.4 37 20 5.33 1.574.69 11.59 36.7 38 27.94 5.99 5.99 11.98 30

Table 14 below shows the content uniformity and physical testing datafor the 100 mg sildenafil based equivalent film products of Examples34-37.

TABLE 14 Content uniformity and physical testing data for 100 mgsildenafil base equivalent film products. Content Uniformity TensileStrength % Elongation @ (n = 10)* PID (n = 3) @ 35% RH max force @ 35%Example Mean Min Max RSD % (n = 3) N/mm² RH 34 101.7 98.5 103.5 1.6 121.44 7.37 35 101.4 98.4 105.1 2.0 24 3.01 4.62 36 106.7 104.9 108.2 1.014 1.65 4.71 37 105.8 103.0 108.6 1.4 29 2.15 4.54

Based on the 140 mg sildenafil citrate examples, Example 34 is the mostdesirable formulation in terms of content uniformity, PID, TensileStrength, and Elongation studies.

Table 15 below shows the physical testing data for the Examples 34, 38,and 39. As can be seen from the comparison of Example 38 (inventive) toExample 39 (comparative) the inventive film product was foundsatisfactory in all of the tested physical parameters. The comparativefilm product, on the other hand, was unsatisfactory in many parameters.Moreover the inventive film product of Example 38 has a PID over 6 timesfaster than that of the comparative film product of Example 39.

TABLE 15 Physical testing data for Examples 34, 38, and 39. Aged ShockPID Example Tack Initial Flex Dry Flex Strength Initial BrittlenessBrittleness Bend Test Sensitive (sec) 34  Not Tacky P P Good P P P P 1238* Not Tacky P P Good P N/A P P 29 39* Not Tacky F F Good F N/A N/A P193 *Examples 38 and 39 were the same size and weight (22 mm × 20 mm;166.67 mg).

Pharmacokinetic Testing

Film products of the invention were tested against Viagra™ Tablets forplasma sildenafil levels. In particular, a 50 mg Viagra™ tablet wastested against film products of the invention including 50 mg baseequivalent of sildenafil as sildenafil citrate or sildenafil resinate.The test articles were as follows: 1) 50 mg Viagra™ tablet, 2) 50 mgbase equivalent sildenafil citrate film product of the invention, 3) 50mg base equivalent sildenafil citrate film product of the invention in agelatin capsule, and 4) 50 mg base equivalent sildenafil resinate filmproduct of the invention. In each instance the test article was placedin the back of the mouth of beagle dogs.

Blood was collected from the beagle dogs at various times and analyzedfor the plasma level of sildenafil.

The results are shown in FIGS. 3-11. In particular, FIGS. 3-6 show theplasma sildenafil levels for individual dogs for each of the 4 testarticles, respectively. FIGS. 7-10 show the mean plasma sildenafillevels for each of the 4 test articles, respectively. FIGS. 11 and 12show a comparison of the mean plasma sildenafil levels for the testarticles.

The test articles had the following pharmacokinetic profiles:

TABLE 16 Pharmacokinetic testing results for sildenafil citrate film, 50mg VIAGRA ™ tablet, and an oral solution of sildenafil citrate.AUC_(0-30 min) AUC_(0-2 hr) AUC_(0-10 hr) C_(MAX) T_(MAX) Dosage Form(ng/ml · hr) (ng/ml · hr) (ng/ml · hr) (ng/mL) (Minutes) VIAGRA ™ Tablet29.62 546.6 2584 550.7 120 Sildenafil Citrate 160.0 982.1 3062 616.3  30Film Sildenafil Citrate 55.52 964.9 3581 758.0 120 Film/Capsule^(†) 0.1NHCl N/A N/A  842 117    66 Solution* at (3368) (468)   (median) 1.0mg/kg (Normalized to 4 mg/kg) ^(†)Average dose about 4.0 mg/kg. *Walker,et al., “Pharmacokinetics and Metabolism of Sildenafil in Mouse, Rat,Dog, and Man,” Xenobiotica 29(3): 297-310 (1999).

Compared to the 50 mg VIAGRA™ tablet, the sildenafil citrate lingualfilm demonstrated a 5-fold increase in systemic exposure at 30 minutespost-dosing. Moreover, the sildenafil citrate film showed a fasterT_(max) (30 minutes) as compared to the VIAGRA™ tablet (2 hours) and theoral solution (about 1 hour). The C_(max) values for the 50 mg VIAGRA™tablet and the sildenafil citrate lingual film were similar. Finally,the sildenafil citrate lingual film had a higher (1.2 times) overallsystemic exposure (AUC_(0-10 hr)) as compared to the 50 mg VIAGRA™tablet.

Sildenafil citrate films as prepared above in Example 33 were tested forstability up to 3 months. The results of this testing are shown inTables 17 and 18.

TABLE 17 Stability testing results for sildenafil citrate film.Degradation Products Assay of Individual API (% Unspecified TotalStorage Sampling Label RRT = Degradation Conditions Time Claim) 0.36 (%)Products (%) Initial T = 0 104.3 0.45 0.45 25° C./60% RH 2 Weeks 103.90.54 0.54 4 Weeks 105.9 0.39 0.39 3 Months 103.8 0.36 0.36 40° C./75% RH1 Week 103.9 0.44 0.44 2 Weeks 105.0 0.58 0.58 4 Weeks 104.5 0.36 0.36 3Months 105.6 0.36 0.36

The Unspecified Impurity (Table 17) detected was identified by spectralanalysis to be a component of the cherry flavor used in the film. It isnot a degradation product of the active (sildenafil citrate). Therefore,no degradation was detected greater than or equal to the limit ofquantitation (0.1%). Accordingly, no degradation of active for thisformulation was detected for up to 3 months at both 25° C. and 60%relative humidity and 40° C. and 75% relative humidity in real timedata.

The assay results remained consistent which shows a mass balance. Thedissolution results remained consistent which shows no slowing down ofthe dissolution rate. Overall, the data for this film supports aconclusion that the formulation (50 mg sildenafil based) is stablestability for up to 3 months at both 25° C. 60% relative humidity and40° C. 75% relative humidity in terms of both assay/impurity level anddissolution. (See FIG. 13.)

Example 40 Pregabalin 150 mg

A film product of the invention was prepared as described above with theingredients set forth in the table.

TABLE 19 Film product of the invention with 150 mg Pregabalin. Dry BasisDry Basis Wet Basis Weight Composition (% w/w) (mg/film) (% w/w) Charged(g) Pregabalin 66.67 150.00 29.44 50.00 pH Adjuster 5.20 11.70 2.29 3.90Glycerin 1.04 2.35 0.46 0.78 Antifoaming Agent 1.32 2.98 0.58 0,.99Starch Derivative 0.67 1.50 0.29 0.50 Artificial Sweetener 0.73 1.650.32 0.55 Monosaccharide 0.33 0.75 0.15 0.25 Sweetener Xylitol 4.6510.46 2.05 3.49 Polyether 1.00 2.25 0.44 0.75 Flavoring Agent 3.97 8.902.38 4.05 Pullulan 7.19 16.18 3.18 5.39 Binder 7.24 16.28 3.20 5.42 Sum100.00 225.00 44.78 76.07 Water Purified 55.20 93.75 Total 100.00 225.00100.00 169.83

Example 41 Tadalafil 5 mg, 10 mg, and 20 mg

A film products of the invention are prepared as described above withthe ingredients set forth in the table.

TABLE 20 Film product of the invention with 5 mg, 10 mg, or 20 mgtadalafil. 5 mg film 10 mg film 20 mg film Composition (% w/w) (% w/w)(% w/w) Tadalafil 6.02 11.35 20.38 Monosaccharide Sweetener 1.42 1.341.20 Pullulan 36.74 34.65 31.12 Xylitol 13.98 13.19 11.84 ArtificialSweetener 1.78 1.68 1.51 Starch Derivative 2.74 2.58 2.32 Glycerin 4.113.87 3.48 Antifoaming agent 4.11 3.87 3.48 Opacifier 5.82 5.49 4.93Polyether 0.26 0.25 0.22 Citric Acid 12.31 11.61 10.43 Colorant 0.190.18 0.16 Flavoring Agent 10.53 9.94 8.92 Sum 100.00 100.00 100.00

Example 42 Content Uniformity of 100 mg Sildenafil Oral Soluble Films

2 Separate batches of films of the invention were prepared as describedabove with the ingredients set forth in Table 21 (Batch A) and Table 22(Batch B) below:

Batch A:

TABLE 21 Film product of the invention with 100 mg Sildenafil baseequivalent. Dry Basis Dry Basis Wet Basis Component (% w/w) (mg/film) (%w/w) Sildenafil Citrate 65.05 140.00 33.29 Monosaccharide Sweetener 0.541.16 0.28 Pullulan 12.77 27.47 6.53 Xylitol 5.31 11.43 2.72 ArtificialSweetener 0.67 1.45 0.35 Starch Derivative 1.04 2.23 0.53 Glycerin 1.553.35 0.80 Antifoaming Agent 1.55 3.35 0.80 Opacifier 0.78 1.67 0.40Polyether 0.99 2.14 0.51 Citric Acid 0.05 0.11 0.03 Colorant 0.07 0.150.04 Flavoring Agent 5.96 12.83 3.05 Carboxymethylcellulose 2.98 6.411.52 Sodium Chloride 0.68 1.47 0.35 Sum 100 215.22 51.20 Water Purified48.83 Total 100 215.22 100

Batch B:

TABLE 22 Film product of the invention with 100 mg Sildenafil baseequivalent. Dry Basis Dry Basis Wet Basis Component (% w/w) (mg/film) (%w/w) Sildenafil Citrate 65.50 140.00 33.52 Monosaccharide Sweetener 0.541.16 0.28 Pullulan 15.76 33.69 8.07 Xylitol 5.35 11.43 2.74 ArtificialSweetener 0.68 1.45 0.35 Starch Derivative 1.05 2.23 0.53 Glycerin 1.573.35 0.80 Antifoaming Agent 1.57 3.35 0.80 Opacifier 0.78 1.67 0.40Polyether 1.00 2.14 0.51 Citric Acid 0.05 0.11 0.03 Colorant 0.07 0.160.04 Flavoring Agent 6.00 12.83 3.07 Carboxymethylcellulose 0.09 0.190.05 Sum 100 213.76 51.17 Water Purified 48.83 Total 100 213.76 100The films of Batch A had a moisture content of 3.94% wt and the films ofBatch B had a moisture content of 3.93% wt based on the total weight ofthe film.

Ten individual unit doses were sampled from each of the 2 batches of thefilm. Each sampled individual unit dose had a desired amount (e.g., adosage amount or label claim amount) of 140 mg of sildenafil citrate(equivalent to 100 mg of sildenafil base). The content of sildenafil ineach sample was determined. The result for each of the sampledindividual unit dose is reported below in Tables 23 and 24:

Batch A

TABLE 23 Sample % wt of Desired Amount 1 100.9 2 96.1 3 92.5 4 97.1 598.4 6 97.2 7 99.1 8 97.2 9 97.1 10 100.0

Batch B

TABLE 24 Sample % wt of Desired Amount 1 99.9 2 106.8 3 110.6 4 103.8 5102.2 6 99.1 7 105.2 8 106.0 9 105.2 10 109.4

The appropriate statistical analysis was carried out for each batch andthe results were as follows:

Batch A:

-   Average % wt of Desired Amount=97.5%-   SD=2.3%-   RSD=2.4%

Batch B:

-   Average % wt of Desired Amount=104.8%-   SD=2.3%-   RSD=2.4%

This content uniformity testing demonstrates that substantially equallysized individual dosage units of the films according to the inventioncontain an amount of active that varies by no more than 10% by weightfrom the desired amount, dosage amount, or drug label claim amount ofthe active.

While there have been described what are presently believed to be thecertain desirable embodiments of the invention, those skilled in the artwill realize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended toinclude all such changes and modifications as fall within the true scopeof the invention.

What is claimed is:
 1. A film product comprising: a. at least one linearpolysaccharide; b. a therapeutically effective amount of at least oneactive component; and c. at least one plasticizer.
 2. The film productaccording to claim 1, wherein the at least one active component isselected from the group consisting of antimicrobial agents,non-steroidal anti-inflammatory drugs, anti-tussives, decongestants,antihistamines, expectorants, anti-diarrheals, H₂ antagonists, protonpump inhibitors, general non-selective CNS depressants, generalnon-selective CNS stimulants, selective CNS functional modifiers,anti-parkinsonism drugs, narcotics, analgesics, erectile dysfunctiontherapeutic actives, PDE5 inhibitors, anti-pyretics,psychopharmacological drugs and combinations thereof.
 3. The filmproduct according to claim 1, wherein the at least one active componentis an erectile dysfunction therapeutic active.
 4. The film productaccording to claim 1, wherein the at least one linear polysaccharide isa polysaccharide with an alpha 1,4 or and alpha 1,6 glycosidic linkage.5. The film product according to claim 1, wherein the at least onelinear polysaccharide is selected from the group consisting of pullulan,elsinan, and combinations thereof.
 6. The film product of claim 1,further comprising an additional film-forming polymer.
 7. The filmproduct of claim 6, wherein the additional film-forming polymer isselected from the group consisting of hydroxypropylmethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, ethyl cellulose, hydroxypropyl ethyl cellulose, celluloseacetate phthalate, hydroxypropyl methyl cellulose phthalate, sodiumalginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum,acacia gum, arabic gum, starch, gelatin, and combinations thereof. 8.The film product according to claim 1, wherein the plasticizer isxylitol, glycerin, or a combination thereof.
 9. The film productaccording to claim 1, wherein i) the film product has a total polymercontent; ii) the plasticizer is xylitol, and iii) the xylitol is presentin an amount of about 10% to about 40% by weight based on the combinedweight of the xylitol and the total polymer content.
 10. The filmproduct according to claim 1, wherein i) the film product has a totalpolymer content; ii) the plasticizer is a combination of xylitol andglycerin; and iii) the amount of glycerin is about equal to or less thanthe amount of xylitol by weight; and iii) the combination of glycerinand xylitol is present in an amount of about 40% or less by weight basedon the combined weight of the xylitol, glycerin, and total polymercontent.
 11. The film product according to claim 1, wherein i) the filmproduct has a total polymer content; ii) the plasticizer is glycerin,and iii) the glycerin is present in an amount of about 15% to about22.5% by weight based on the combined weight of the xylitol and thetotal polymer content.
 12. The film product according to claim 1,wherein i) the film product has a total polymer content; ii) theplasticizer is glycerin, and iii) the glycerin is present in an amountof about 18% to about 21% by weight based on the combined weight of thexylitol and the total polymer content.
 13. The film product according toclaim 1, further comprising an acid.
 14. The film product according toclaim 1, further comprising an acid selected from the group consistingof citric acid, formic acid, acetic acid, propionic acid, ascorbic acid,lactic acid, malic acid, tartaric acid, and combinations thereof. 15.The film product according to claim 1, further comprising citric acid,wherein i) the film product has a total polymer content; ii) theplasticizer is xylitol, iii) the amount of citric acid is about equal toor less than the amount of xylitol by weight; and iv) the xylitol ispresent in an amount of about 10% to about 40% by weight based on thecombined weight of the xylitol and the total polymer content.
 16. Thefilm product according to claim 1, further comprising citric acid,wherein i) the film product has a total polymer content; ii) theplasticizer is a combination of xylitol and glycerin; and iii) thecombination of glycerin, xylitol, and citric acid is present in anamount of about 45% or less by weight based on the combined weight ofthe xylitol, glycerin, and total polymer content.
 17. The film productaccording to claim 1, wherein the film product comprises less than about5% water by weight based on the total weight of the film product. 18.The film product according to claim 1, wherein the film productcomprises less than about 2% water by weight based on the total weightof the film product.
 19. The film product according to claim 1, whereinthe amount of active component is about 40% or greater by weight basedon the dry weight of the film product.
 20. The film product according toclaim 1, wherein the amount of active component is about 50% or greaterby weight based on the dry weight of the film product.
 21. The filmproduct according to claim 1, wherein the amount of active component isabout 55% or greater by weight based on the dry weight of the filmproduct.
 22. The film product according to claim 1, wherein the amountof active component is about 60% or greater by weight based on the dryweight of the film product.
 23. The film product according to claim 1,wherein the film product has a partial immersion dissolution time ofabout 1 to about 60 seconds.
 24. The film product according to claim 1,wherein the film product has a partial immersion dissolution time ofabout 2 to about 30 seconds.
 25. The film product according to claim 1,wherein the film product has a partial immersion dissolution time ofabout 2 to about 10 seconds.
 26. The film product according to claim 1,wherein the film product has a partial immersion dissolution time ofabout 10 to about 30 seconds.
 27. The film product according to claim 1,wherein the film product has a tensile strength of about 0.8 N/mm orgreater.
 28. The film product according to claim 1, wherein the filmproduct has a tensile strength of about 1 N/mm or greater.
 29. A filmproduct comprising: a. pullulan; b. a therapeutically effective amountof sildenafil or a pharmaceutically acceptable salt thereof; and c. atleast one plasticizer.
 30. A film product comprising: a. at least onelinear polysaccharide; b. a therapeutically effective amount of apregabalin; and c. at least one plasticizer.
 31. A film productcomprising: a. pullulan; b. a therapeutically effective amount oftadalafil; and c. at least one plasticizer.